Isoxazolo-pyridine derivatives

ABSTRACT

The present invention is concerned with isoxazole-pyridine derivatives of formula I 
                         
wherein X, R 1  to R 6  are as described herein. The compounds are active on the GABA A α5 receptor binding site and useful for the treatment of cognitive disorders, such as Alzheimer&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/370,444, filed Feb. 10, 2012, which is a continuation of U.S.application Ser. No. 12/325,293, filed Dec. 1, 2008, now abandoned,which claims the benefit of European Patent Application No. 07122240.0,filed Dec. 4, 2007. Each of these applications is hereby incorporated byreference herein in its entirety.

BACKGROUND OF THE INVENTION

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyricacid (GABA), are divided into two main classes: (1) GABA A receptors,which are members of the ligand-gated ion channel superfamily and (2)GABA B receptors, which are members of the G-protein linked receptorfamily. The GABA A receptor complex which is a membrane-boundheteropentameric protein polymer is composed principally of α, β and γsubunits.

Presently a total number of 21 subunits of the GABA A receptor have beencloned and sequenced. Three types of subunits (α, β and γ) are requiredfor the construction of recombinant GABA A receptors which most closelymimic the biochemical, electrophysiological and pharmacologicalfunctions of native GABA A receptors obtained from mammalian braincells. There is strong evidence that the benzodiazepine binding sitelies between the α and γ subunits. Among the recombinant GABA Areceptors, α1β2γ2 mimics many effects of the classical type-I BzRsubtypes, whereas α2β2γ2, α3β2γ2 and α5β2γ2 ion channels are termedtype-II BzR.

It has been shown by McNamara and Skelton in Psychobiology, 21:101-108that the benzodiazepine receptor inverse agonist β-CCM enhance spatiallearning in the Morris watermaze. However, β-CCM and other conventionalbenzodiazepine receptor inverse agonists are proconvulsant or convulsantwhich prevents their use as cognition enhancing agents in humans. Inaddition, these compounds are non-selective within the GABA A receptorsubunits, whereas a GABA A α5 receptor partial or full inverse agonistwhich is relatively free of activity at GABA A α1 and/or α2 and/or α3receptor binding sites can be used to provide a medicament which isuseful for enhancing cognition with reduced or without proconvulsantactivity. It is also possible to use GABA A α5 inverse agonists whichare not free of activity at GABA A α1 and/or α2 and/or α3 receptorbinding sites but which are functionally selective for α5 containingsubunits. However, inverse agonists which are selective for GABA A α5subunits and are relatively free of activity at GABA A α1, α2 and α3receptor binding sites are preferred.

SUMMARY OF THE INVENTION

The present invention provides isoxazole-pyridine derivatives havingaffinity and selectivity for GABA A α5 receptor binding site, theirmanufacture, pharmaceutical compositions containing them and their useas cognitive enhancer or for the treatment of cognitive disorders likeAlzheimer's disease.

In particular, the present invention provides isoxazole-pyridinederivatives of formula I

wherein X, R¹ to R⁶ are as described in claim 1.

The most preferred indication in accordance with the present inventionis Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

As used herein, the term “alkyl” denotes a saturated straight- orbranched-chain hydrocarbon group containing from 1 to 7 carbon atoms,for example, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, tert-butyl and the like. Preferred alkyl groups are groupswith 1 to 4 carbon atoms.

The term “halo” or “halogen” denotes chloro, iodo, fluoro and bromo.

The term “halo-C₁₋₇-alkyl”, “C₁₋₇-haloalkyl” or “C₁₋₇-alkyl optionallysubstituted with halo” denotes a C₁₋₇-alkyl group as defined abovewherein at least one of the hydrogen atoms of the alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Examples of halo-C₁₋₇-alkyl include but are not limited tomethyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s), inparticular one, two or three fluoro or chloro, as well as those groupsspecifically illustrated by the examples herein below. Among thepreferred halo-C₁₋₇-alkyl groups are difluoro- or trifluoromethyl or-ethyl.

The term “hydroxy-C₁₋₇-alkyl”, “C₁₋₇-hydroxyalkyl” or “C₁₋₇-alkyloptionally substituted with hydroxy” denotes a C₁₋₇-alkyl group asdefined above wherein at least one of the hydrogen atoms of the alkylgroup is replaced by a hydroxy group. Examples of hydroxy-C₁₋₇-alkylinclude but are not limited to methyl, ethyl, propyl, isopropyl,isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one ormore hydroxy group(s), in particular with one, two or three hydroxygroups, preferably with one hydroxy group, as well as those groupsspecifically illustrated by the examples herein below.

The term “cyano-C₁₋₇-alkyl”, “C₁₋₇-cyanoalkyl” or “C₁₋₇-alkyl optionallysubstituted with cyano” denotes a C₁₋₇-alkyl group as defined abovewherein at least one of the hydrogen atoms of the alkyl group isreplaced by a cyano group. Examples of hydroxy-C₁₋₇-alkyl include butare not limited to methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or morecyano group(s), preferably by one, two or three, and more preferably byone cyano group, as well as those groups specifically illustrated by theexamples herein below.

The term “alkoxy” denotes a group —O—R wherein R is alkyl as definedabove.

The term “aryl” refers to a monovalent aromatic carbocyclic ring system,preferably to phenyl or naphthyl, and more preferably to phenyl. Aryl isoptionally substituted as described herein. If not further indicated,phenyl may optionally be substituted with one or more, in particularwith 1, 2, or 3, and more preferably with 1 or 2 substituents selectedfrom halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, and C₃₋₇cycloalkyl.

The term “aromatic” means aromatic according to Hückel's rule. A cyclicmolecule follows

Hückel's rule when the number of its n-electrons equals 4n+2 where n iszero or any positive integer.

The term “C₁₋₇-haloalkoxy” or “halo-C₁₋₇-alkoxy” denotes a C₁₋₇-alkoxygroup as defined above wherein at least one of the hydrogen atoms of thealkoxy group is replaced by a halogen atom, preferably fluoro or chloro,most preferably fluoro. Examples of halo-C₁₋₇-alkoxy include but are notlimited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl,tert-butyl, pentyl or n-hexyl substituted by one or more Cl, F, Br or Iatom(s), in particular one, two or three fluoro or chloro atoms, as wellas those groups specifically illustrated by the examples herein below.Among the preferred halo-C₁₋₇-alkoxy groups are difluoro- ortrifluoro-methoxy or -ethoxy substituted as described above, preferably—OCF₃.

The term “cycloalkyl” refers to a monovalent saturated cyclichydrocarbon radical of 3 to 7 ring carbon atoms, preferably 3 to 6carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

The term “heterocycloalkyl” refers to a monovalent 3 to 7 memberedsaturated monocyclic ring containing one, two or three ring heteroatomsselected from N, O and S. One or two ring heteroatoms are preferred.Preferred are 4 to 6 membered heterocycloalkyl or 5 to 6 memberedheterocycloalkyl, each containing one or two ring heteroatoms selectedfrom N, O and S. Examples for heterocycloalkyl moieties aretetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, piperidinyl, or piperazinyl. “Heterocycloalkyl” ishence a subgroup of “heterocyclyl” as defined below. Heterocycloalkyl isoptionally substituted as described herein.

The term “heteroaryl” refers to a monovalent aromatic 5- or 6-memberedmonocyclic ring containing one, two, or three ring heteroatoms selectedfrom N, O, and S, the remaining ring atoms being C. Preferably, the 5-or 6-membered heteroaryl ring contains one or two ring heteroatoms.6-membered heteroaryl are preferred. Examples for heteroaryl moietiesinclude but are not limited to furanyl, thiophenyl, pyridinyl,pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, 1,2,4-oxadiazolyl, or1,3,4-oxadiazolyl. Preferred heteroaryl groups are pyridinyl, pyrazolyl,isoxazolyl, thiazolyl, or 1,2,4-oxadiazolyl.

The term “heterocyclyl” or “heterocyclyl moiety” refers to a monovalentsaturated or partially saturated 3- to 7-membered monocyclic or 9- to10-membered bicyclic ring system wherein one, two, three or four ringcarbon atoms have been replaced by N, O or S, and with the attachmentpoint on the saturated or partially unsaturated ring of said ringsystem. Such bicyclic heterocyclyl moieties hence include aromatic ringsannelated to saturated rings. Where applicable, “heterocyclyl moiety”further includes cases where two residues R′ and R″ together with thenitrogen to which they are bound form such a heterocyclyl moiety.Examples for heterocyclyl include but are not limited totetrahydropyridinyl, isochromanyl, chromanyl, oxethanyl, isoxazolidinyl,dihydropyridazinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, piperazinyl, pyrrolidinyl, as wellas morpholinyl, thiomorpholinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidinyl, hexahydrothiopyranyl, or6-oxa-3-aza-bicyclo[3.1.1]heptanyl.

Examples for substituted heterocyclyl include, but are not limited tooxetan-3-ol, 3-oxoisazolidinyl, 3-oxo-dihydropyridazinyl,6-methyl-3-oxo-dihydropyridazinyl, 2,2-dimethyl-tetrahydropyranyl,tetrahydrothiopyranyl dioxide, N-methyl-piperidinyl,N-ethyl-piperidinyl, N-isopropyl-piperidinyl, N-benzyl-piperidinyl,piperidin-1-yl-acetic t-butyl ester, piperidin-1-yl-acetic acid ethylester, piperidin-1-yl-acetic acid,N-(1-ethylcarbamoylmethyl-piperidinyl),N-(1-cyclopropylcarbamoylmethylpiperidinyl),N-{1[(2,2,2-trifluoro-ethylcarbamoyl)methyl]piperidinyl},N-{1-[(2-hydroxyethylcarbamoyl)methyl]piperidinyl},N-{1-[(tetrahydropyran-4-ylcarbamoyl)methyl]piperidinyl}, as well as2-oxo-pyrrolidinyl, 4,4-difluoro-piperidinyl, dioxothiomorpholinyl,3,3-dimethyl-morpholinyl, or 1-methyl-1,2,3,6-tetrahydropyridinyl.

The term “spirocyclic heterocycle” denotes a saturated bicyclic ringsystem wherein the two rings have one carbon atom in common. Thespirocyclic heterocycle may be from 7- to 12-membered, preferably from7- to 11-membered. As an example for a spirocyclic heterocycle,2-oxa-6-aza-spiro[3.3]heptyl may be mentioned. The spirocyclicheterocycle may be optionally substituted as described herein.

The term “oxo” when referring to substituents on heterocycloalkyl,heterocyclyl or on a heterocycle means that an oxygen atom is attachedto the ring. Thereby, the “oxo” may either replace two hydrogen atoms ona carbon atom, or it may simply be attached to sulfur, so that thesulfur exists in oxidized form, i.e. bearing one or two oxygens.

When indicating the number of substituents, the term “one or more” meansfrom one substituent to the highest possible number of substitution,i.e. replacement of one hydrogen up to replacement of all hydrogens bysubstituents. Thereby, one, two or three substituents are preferred.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable salt” or “pharmaceuticallyacceptable acid addition salt” embraces salts with inorganic and organicacids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoricacid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid,succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonicacid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

In general, the nomenclature used in this application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

In detail, the present invention relates to compounds of the generalformula (I)

wherein

-   -   X is O or NH;    -   R¹ is phenyl, pyridinyl, or pyrimidinyl, each optionally        substituted with 1, 2 or 3 halo,    -   R² is H, CH₃, or CF₃;    -   R³, R⁴, R⁵, and R⁶ each are independently        -   H,        -   C₁₋₇alkyl, optionally substituted with one or more halo,            cyano, or hydroxy,        -   C₁₋₇alkoxy, optionally substituted with one or more halo,        -   CN,        -   halo,        -   NO₂,        -   S—C₁₋₇alkyl,        -   S(O)—C₁₋₇alkyl        -   benzyloxy, optionally substituted with one or more E,        -   —C(O)—R^(a), wherein R^(a) is hydroxy, C₁₋₇alkoxy,            C₁₋₇alkyl, phenoxy or phenyl,        -   3- to 7-membered heterocyclyl, optionally substituted with            one or more A,        -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each            independently            -   H,            -   C₁₋₇alkyl, optionally substituted with one or more halo,                methyl, —(CH₂)_(L)-hydroxy,                -   or cyano,            -   —(CH₂)_(t)—C₃₋₇cycloalkyl, optionally substituted by one                or more B,                -   and t is 0, 1, 2, 3, 4, 5 or 6,            -   —(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3, 4, 5 or 6,            -   —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl or                C₁₋₄alkyl, and R^(ii) is H or C₁₋₇alkyl,            -   —S(O)₂—C₁₋₇alkyl,            -   —S(O)₂—C₃₋₇cycloalkyl,            -   —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3, and                R^(iii) is H or C₁₋₇alkyl,            -   —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl, each                optionally substituted by one or more E, and wherein w                is 0, 1, 2, 3, or 4,            -   —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4,                and wherein heterocyclyl is optionally substituted by                one or more                -   oxo,                -   C₁₋₇alkyl,                -   C₃₋₇cycloalkyl, optionally substituted with one or                    more B,                -   CN,                -   benzyl, optionally substituted with one or more E,                -   —(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4,                    and R^(iv) is hydroxy, C₁₋₇alkyl,                -    or C₁₋₇alkoxy,                -   —(CH₂)_(z)—C(O)NR^(v)R^(vi),                    —(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or                -    —(CH₂), NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z is                    0, 1, 2, 3 or 4,                -    and R^(v) and R^(vi) are independently                -    hydrogen,                -    C₁₋₇alkyl, optionally substituted by one or more                    halo, OH or CN,                -    C₃₋₇cycloalkyl, optionally substituted by one or                    more B,                -    5- or 6-membered heterocyclyl, optionally                    substituted by one or more A, or                -    R^(v) and R^(vi) together with the nitrogen to                    which they are bound form a 5- or 6-membered                    heterocycloalkyl, optionally substituted by one or                    more A, or            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a heterocyclyl or heteroaryl moiety,                optionally substituted with one or more A, or            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a 7- to 12-membered spirocyclic                heterocycle, optionally substituted with one or more A;            -   with the proviso that R^(b) and R^(c) are not                simultaneously H,    -   A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,        C₁₋₇hydroxyalkyl, halo, or CN;    -   B is halo, hydroxy, CN, C₁₋₄alkyl, benzyloxy, or C₁₋₄haloalkyl;        and    -   E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,        C₁₋₇haloalkyl,        -   C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or            C₃₋₇cycloalkyl;            or a pharmaceutically acceptable salt thereof.

In certain embodiments of the compound of formula I, X is O or NH. Eachof these alternatives may be combined with any other embodiment asdisclosed herein.

Further, it is to be understood that every embodiment relating to aspecific residue R¹ to R⁶ as disclosed herein may be combined with anyother embodiment relating to another residue R¹ to R⁶ as disclosedherein.

In certain embodiments of the compound of formula I, R¹ is phenyl,pyridinyl, or pyrimidinyl, each optionally substituted with one, two orthree halo. Preferred halo substituents are chloro and fluoro.Preferably, phenyl is optionally substituted with one, two or three,more preferably with one or two halo substituents selected from chloroand fluoro. Thereby, the halo substituents are located at the ortho,meta or para-position or at the meta and para position of the phenylring in respect to the attachment to the isoxazole.

In certain embodiments of the compound of formula I, R² is methyl ortrifluoromethyl.

In certain embodiments of the compound of formula I, R³, R⁴, R⁵, and R⁶are as defined above.

In certain embodiments of the compound of formula I, R³ is H, halo, CNor C₁₋₇alkyl. Preferably, R³ is H, CN or C₁₋₄alkyl. More preferably, R³is H, CN or methyl.

In certain embodiments of the compound of formula I, R⁶ is H, halo, CNor C₁₋₇alkyl. Preferably, R⁶ is H, halo or C₁₋₄alkyl, more preferably,R⁶ is H, Br or C₁₋₄alkyl. Even more ore preferably, R⁶ is H, Br ormethyl.

In certain embodiments of the compound of formula I, R⁴ and R⁵ are eachindependently as defined above.

In certain embodiments of the compound of formula I, R⁴ and R⁵ are eachindependently as defined above and R³ and R⁶ are each independently H,halo, CN or C₁₋₇alkyl.

In certain embodiments of the compound of formula I, R⁴ or R⁵, and inparticular R⁴ are

-   -   H,    -   C₁₋₇alkyl, optionally substituted with one or more halo, cyano,        or hydroxy,    -   C₁₋₇alkoxy, optionally substituted with one or more halo,    -   CN,    -   halo,    -   NO₂,    -   S—C₁₋₇alkyl,    -   S(O)—C₁₋₇alkyl    -   benzyloxy, optionally substituted with one or more E,    -   —C(O)—R^(a), wherein R^(a) is hydroxy, C₁₋₇alkoxy, C₁₋₇alkyl,        phenoxy or phenyl,    -   3- to 7-membered heterocyclyl, optionally substituted with one        or more A,    -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each        independently        -   H,        -   C₁₋₇alkyl, optionally substituted with one or more halo,            methyl, —(CH₂)_(t)-hydroxy,            -   or cyano,        -   —(CH₂)_(t)—C₃₋₇cycloalkyl, optionally substituted by one or            more B,            -   and t is 0, 1, 2, 3, 4, 5 or 6,        -   —(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3, 4, 5 or 6,        -   —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl or            C₁₋₄alkyl, and R^(ii) is H or C₁₋₇alkyl,        -   —S(O)₂—C₁₋₇alkyl,        -   —S(O)₂—C₃₋₇cycloalkyl,        -   —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3, and R^(iii)            is H or C₁₋₇alkyl,        -   —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl, each optionally            substituted by one or more E, and wherein w is 0, 1, 2, 3,            or 4,        -   —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and            wherein heterocyclyl is optionally substituted by one or            more            -   oxo,            -   C₁₋₇alkyl,            -   C₃₋₇cycloalkyl, optionally substituted with one or more                B,            -   CN,            -   benzyl, optionally substituted with one or more E,            -   —(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4, and                R^(iv) is hydroxy, C₁₋₇alkyl,                -   or C₁₋₇alkoxy,            -   —(CH₂)_(z)—C(O)NR^(v)R^(vi),                —(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or                -   —(CH₂)_(z)NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z                    is 0, 1, 2, 3 or 4,            -   and R^(v) and R^(vi) are independently                -   hydrogen,                -   C₁₋₇alkyl, optionally substituted by one or more                    halo, OH or CN,                -   C₃₋₇cycloalkyl, optionally substituted by one or                    more B,                -   5- or 6-membered heterocyclyl, optionally                    substituted by one or more A, or                -   R^(v) and R^(vi) together with the nitrogen to which                    they are bound form a 5- or 6-membered                    heterocycloalkyl, optionally substituted by one or                    more A,        -   R^(b) and R^(c) together with the nitrogen to which they are            bound form a heterocyclyl or heteroaryl moiety, optionally            substituted with one or more A, or        -   R^(b) and R^(c) together with the nitrogen to which they are            bound form a 7- to 12-membered spirocyclic heterocycle,            optionally substituted with one or more A;        -   with the proviso that R^(b) and R^(c) are not simultaneously            H,            A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,            C₁₋₇hydroxyalkyl, halo, or CN;            B is halo, hydroxy, CN, C₁₋₄alkyl, benzyloxy, or            C₁₋₄haloalkyl; and            E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,            C₁₋₇haloalkyl,    -   C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or        C₃₋₇cycloalkyl;        or a pharmaceutically acceptable salt thereof.

In certain embodiments of the compound of formula I, R⁴ is

-   -   H,        -   C₁₋₇alkyl, optionally substituted with one or more halo,            cyano, or hydroxy,        -   C₁₋₇alkoxy, optionally substituted with one or more halo,        -   CN,        -   halo,        -   NO₂,        -   S—C₁₋₇alkyl,        -   S(O)—C₁₋₇alkyl,        -   benzyloxy, optionally substituted with one or more E,        -   —C(O)—R^(a), wherein R^(a) is hydroxy, C₁₋₇alkoxy,            C₁₋₇alkyl, phenoxy or phenyl,        -   3- to 7-membered heterocyclyl, optionally substituted with            one or more A,        -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each            independently            -   H,            -   C₁₋₇alkyl, optionally substituted with one or more halo,                methyl, —(CH₂)_(t)-hydroxy,                -   or cyano,            -   —(CH₂)_(t)—C₃₋₇cycloalkyl, optionally substituted by one                or more B,                -   and t is 0, 1, 2, 3, 4, 5 or 6,            -   —(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3, 4, 5 or 6,            -   —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl or                C₁₋₄alkyl, and R^(ii) is H or C₁₋₇alkyl,            -   —S(O)₂—C₁₋₇alkyl,            -   —S(O)₂—C₃₋₇cycloalkyl,            -   —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3, and                R^(iii) is H or C₁₋₇alkyl,            -   —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl, each                optionally substituted by one or more E, and wherein w                is 0, 1, 2, 3, or 4,            -   —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4,                and wherein heterocyclyl is optionally substituted by                one or more                -   oxo,                -   C₁₋₇alkyl,                -   C₃₋₇cycloalkyl, optionally substituted with one or                    more B,                -   CN,                -   benzyl, optionally substituted with one or more E,                -   —(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4,                    and R^(iv) is hydroxy, C₁₋₇alkyl,                -    or C₁₋₇alkoxy,                -   —(CH₂), —C(O)NR^(v)R^(vi),                    —(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or                -    —(CH₂), NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z is                    0, 1, 2, 3 or 4,                -   and R^(v) and R^(vi) are independently                -    hydrogen,                -    C₁₋₇alkyl, optionally substituted by one or more                    halo, OH or CN,                -    C₃₋₇cycloalkyl, optionally substituted by one or                    more B,                -    5- or 6-membered heterocyclyl, optionally                    substituted by one or more A, or                -    R^(v) and R^(vi) together with the nitrogen to                    which they are bound form a 5- or 6-membered                    heterocycloalkyl, optionally substituted by one or                    more A,            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a heterocyclyl or heteroaryl moiety,                optionally substituted with one or more A, or            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a 7- to 12-membered spirocyclic                heterocycle, optionally substituted with one or more A;            -   with the proviso that R^(b) and R^(c) are not                simultaneously H,                A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,                C₁₋₇hydroxyalkyl, halo, or CN;                B is halo, hydroxy, CN, C₁₋₄alkyl, benzyloxy, or                C₁₋₄haloalkyl; and                E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,                C₁₋₇haloalkyl,    -   C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or        C₃₋₇cycloalkyl;        or a pharmaceutically acceptable salt thereof.

In certain embodiments of the compound of formula I, R⁴ is H.

In certain embodiments of the compound of formula I, R⁴ is C₁₋₇alkyl,optionally substituted with one or more halo, cyano, or hydroxy.

In certain embodiments of the compound of formula I, R⁴ is CN.

In certain embodiments of the compound of formula I, R⁴ is halo.

In certain embodiments of the compound of formula I, R⁴ is NO₂.

In certain embodiments of the compound of formula I, R⁴ is —C(O)—R^(a),wherein R^(a) is hydroxy, C₁₋₇alkoxy, C₁₋₇alkyl, phenoxy or phenyl.

In certain embodiments of the compound of formula I, R⁴ is benzyloxy,optionally substituted with one or more E, wherein E is as described asabove.

In certain embodiments of the compound of formula I, R⁴ is 3- to7-membered heterocyclyl, optionally substituted with one or more A.Preferably, R⁴ in such an embodiment is a 3- to 7-memberedheterocycloalkyl, optionally substituted with one or more A. A is asdescribed above. As an example for this embodiment, R⁴ is oxethanyl,substituted with one OH.

In certain embodiments of the compound of formula I, R⁴ is

-   -   —C(O)—NR^(b)R^(c), wherein R^(b) is H or C₁₋₇alkyl and R^(c) is        -   H, with the proviso that R^(b) and R^(c) are not            simultaneously H,        -   C₁₋₇alkyl, optionally substituted with one or more halo,            methyl, —(CH₂)_(t)-hydroxy,            -   or cyano,        -   —CH₂)_(t)—C₃₋₇cycloalkyl, optionally substituted by one or            more B,            -   and t is 0, 1, 2, 3, 4, 5 or 6,        -   —(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3, 4, 5 or 6,        -   —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl or            C₁₋₄alkyl, and R^(ii) is H or C₁₋₇alkyl,        -   —S(O)₂—C₁₋₇alkyl,        -   —S(O)₂—C₃₋₇cycloalkyl,        -   —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3, and R^(iii)            is H or C₁₋₇alkyl,        -   —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl, each optionally            substituted by one or more E, and wherein w is 0, 1, 2, 3,            or 4,        -   —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and            wherein heterocyclyl is optionally substituted by one or            more            -   oxo,            -   C₁₋₇alkyl,            -   C₃₋₇cycloalkyl, optionally substituted with one or more                B,            -   CN,            -   benzyl, optionally substituted with one or more E,            -   —(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4, and                R^(iv) is hydroxy, C₁₋₇alkyl,                -   or C₁₋₇alkoxy,            -   —(CH₂)_(z)—C(O)NR^(v)R^(vi),                —(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or                -   —(CH₂)_(z)NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z                    is 0, 1, 2, 3 or 4,            -   and R^(v) and R^(vi) are independently                -   hydrogen,                -   C₁₋₇alkyl, optionally substituted by one or more                    halo, OH or CN,                -   C₃₋₇cycloalkyl, optionally substituted by one or                    more B,                -   5- or 6-membered heterocyclyl, optionally                    substituted by one or more A, or                -   R^(v) and R^(vi) together with the nitrogen to which                    they are bound form a 5- or 6-membered                    heterocycloalkyl, optionally substituted by one or                    more A,        -   R^(b) and R^(c) together with the nitrogen to which they are            bound form a heterocyclyl or heteroaryl moiety, optionally            substituted with one or more A, or        -   R^(b) and R^(c) together with the nitrogen to which they are            bound form a 7- to 12-membered spirocyclic heterocycle,            optionally substituted with one or more A;        -   with the proviso that R^(b) and R^(c) are not simultaneously            H,            and wherein    -   A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,        C₁₋₇hydroxyalkyl, halo, or CN;    -   B is halo, hydroxy, CN, C₁₋₄alkyl, benzyloxy, or C₁₋₄haloalkyl;        and    -   E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,        C₁₋₇haloalkyl,        -   C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or            C₃₋₇cycloalkyl.

Examples for heteroaryl in this embodiment comprise pyridinyl,pyrazolyl, isoxazolyl, thiazolyl, or 1,2,4-oxadiazolyl, each optionallysubstituted by one or more E as defined herein.

Examples for heterocyclyl in —(CH₂)_(x)-heterocyclyl comprisetetrahydropyridinyl, isochromanyl, oxethanyl, isoxazolidinyl,dihydropyridazinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, or pyrrolidinyl, each optionallysubstituted as described above.

In certain embodiments of the compound of formula I, R⁴ is—C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) together with the nitrogen towhich they are bound form a heterocyclyl moiety, optionally substitutedwith one or more A as defined herein.

Examples for the heterocyclyl moiety in this embodiment includemorpholinyl, thiomorpholinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazinyl, or4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidinyl, each optionallysubstituted with one or more A as defined herein.

In certain embodiments of the compound of formula I, R⁴ is—C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) together with the nitrogen towhich they are bound form a 7- to 12-membered spirocyclic heterocycle,optionally substituted with one or more A as defined herein.

Examples for a 7-membered spirocyclic heterocycle comprise2-oxa-6-aza-spiro[3.3]heptyl, optionally substituted with one or more Aas defined herein.

In certain embodiments of the compound of formula I, R⁵ is

-   -   H,    -   C₁₋₇alkyl, optionally substituted by one or more halo, hydroxy        or CN,    -   benzyloxy, optionally substituted with one or more E,    -   3- to 7-membered heterocyclyl, optionally substituted with one        or more A,    -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each        independently        -   H,        -   3-7-membered heterocycloalkyl, optionally substituted with            one or more A,            A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,            C₁₋₇hydroxyalkyl, halo, or CN; and            E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,            C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl,    -   C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl.

In certain embodiments of the compound of formula I, R⁵ is

-   -   H,    -   CF₃,    -   benzyloxy,    -   tetrahydropyridinyl optionally substituted by one methyl,    -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each        independently H,    -   or morpholinyl.

In certain embodiments of the invention, R⁴ is as described in any ofthe embodiments above, R⁵ is H or CF₃, R³ and R⁶ are H, halo, CN orC₁₋₇alkyl.

In certain embodiments of the invention, R³, R⁴, R⁵ and R⁶ are notsimultaneously hydrogen.

A certain embodiment of the invention comprises the compound of formulaI

wherein

-   -   X is O or NH;    -   R¹ is phenyl, pyridinyl, or pyrimidinyl, each optionally        substituted with 1, 2 or 3 halo,    -   R² is H or CH₃ or CF₃;    -   R⁴ is        -   H,        -   C₁₋₇alkyl, optionally substituted with one or more halo,            cyano, or hydroxy,        -   C₁₋₇alkoxy, optionally substituted with one or more halo,        -   CN,        -   halo,        -   NO₂,        -   S—C₁₋₇alkyl,        -   S(O)—C₁₋₇alkyl,        -   benzyloxy, optionally substituted with one or more E,        -   —C(O)—R^(a), wherein R^(a) is hydroxy, C₁₋₇alkoxy,            C₁₋₇alkyl, phenoxy or phenyl,        -   3- to 7-membered heterocyclyl, optionally substituted with            one or more A,        -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each            independently            -   H,            -   C₁₋₇alkyl, optionally substituted with one or more halo,                methyl, —(CH₂)_(t)-hydroxy,                -   or cyano,            -   —(CH₂)_(L)—C₃₋₇cycloalkyl, optionally substituted by one                or more B,                -   and t is 0, 1, 2, 3, 4, 5 or 6,            -   —(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3, 4, 5 or 6,            -   —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl or                C₁₋₄alkyl, and R^(ii) is H or C₁₋₇alkyl,            -   —S(O)₂—C₁₋₇alkyl,            -   —S(O)₂—C₃₋₇cycloalkyl            -   —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3, and                R^(iii) is H or C₁₋₇alkyl,            -   —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl, each                optionally substituted by one or more E, and wherein w                is 0, 1, 2, 3, or 4,            -   —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4,                and wherein heterocyclyl is optionally substituted by                one or more                -   oxo,                -   C₁₋₇alkyl,                -   C₃₋₇cycloalkyl, optionally substituted with one or                    more B,                -   CN,                -   benzyl, optionally substituted with one or more E,                -   —(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4,                    and R^(iv) is hydroxy, C₁₋₇alkyl, or C₁₋₇alkoxy,                -   —(CH₂)_(z)—C(O)NR^(v)R^(vi),                    —(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or                    —(CH₂)_(z)NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z                    is 0, 1, 2, 3 or 4,                -   and R^(v) and R^(vi) are independently                -    hydrogen,                -    C₁₋₇alkyl, optionally substituted by one or more                    halo, OH or CN,                -    C₃₋₇cycloalkyl, optionally substituted by one or                    more B,                -    5- or 6-membered heterocyclyl, optionally                    substituted by one or more A, or                -    R^(v) and R^(vi) together with the nitrogen to                    which they are bound form a 5- or 6-membered                    heterocycloalkyl, optionally substituted by one or                    more A,            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a heterocyclyl or heteroaryl moiety,                optionally substituted with one or more A, or            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a 7- to 12-membered spirocyclic                heterocycle, optionally substituted with one or more A;            -   with the proviso that R^(b) and R^(c) are not                simultaneously H,    -   A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,        C₁₋₇hydroxyalkyl, halo, or CN;    -   B is halo, hydroxy, CN, C₁₋₄alkyl, benzyloxy, or C₁₋₄haloalkyl;    -   E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,        C₁₋₇haloalkyl,        -   C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or            C₃₋₇cycloalkyl;    -   R⁵ is H,        -   C₁₋₇alkyl, optionally substituted by one or more halo,            hydroxy or CN,        -   benzyloxy, optionally substituted with one or more E,        -   3- to 7-membered heterocyclyl, optionally substituted with            one or more A,        -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each            independently            -   H, with the proviso that R^(b) and R^(c) are not                simultaneously H,            -   3-7-membered heterocycloalkyl, optionally substituted                with one or more A,    -   R³ and R⁶ are H, halo, CN or C₁₋₇alkyl;    -   A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,        C₁₋₇hydroxyalkyl, halo, or CN;    -   B is halo, hydroxy, CN, C₁₋₄alkyl, or C₁₋₄haloalkyl; and    -   E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,        C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl,        -   C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl,            or a pharmaceutically acceptable salt thereof.

A further embodiment of the invention are compounds of formula I

wherein

-   -   X is O or NH;    -   R¹ is phenyl, pyridinyl, or pyrimidinyl, each optionally        substituted with 1, 2 or 3 halo,    -   R² is C₁₋₄alkyl or C₁₋₄haloalkyl;    -   R³, R⁴, R⁵, and R⁶ each are independently        -   H,        -   C₁₋₇alkyl, optionally substituted with one or more halo,            cyano, or hydroxy,        -   C₁₋₇alkoxy, optionally substituted with one or more halo,        -   CN,        -   halo,        -   NO₂,        -   benzyloxy, optionally substituted with one or more E,        -   —C(O)—R^(a), wherein R³ is hydroxy, C₁₋₇alkoxy, C₁₋₇alkyl,            phenoxy or phenyl,        -   3- to 7-membered heterocyclyl, optionally substituted with            one or more A,        -   —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are each            independently            -   H,            -   C₁₋₇alkyl, optionally substituted with one or more halo,                hydroxy, or cyano,            -   —(CH₂)_(L)—C₃₋₇cycloalkyl, optionally substituted by one                or more B,                -   and t is 0, 1, 2, 3 or 4,            -   —(CH₂)_(u)—O—C₁₋₇alkyl, wherein L is 2, 3, 4, 5 or 6,            -   —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H or C₁₋₄alkyl,                and R^(ii) is H or C₁₋₇alkyl,            -   —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3, and                R^(iii) is H or C₁₋₇alkyl,            -   —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl, each                optionally substituted by one or more E, and wherein w                is 0, 1, 2, 3, or 4,            -   —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4,                and wherein heterocyclyl is optionally substituted by                one or more                -   oxo,                -   C₁₋₇alkyl,                -   C₃₋₇cycloalkyl, optionally substituted with one or                    more B,                -   CN,                -   benzyl, optionally substituted with one or more E,                -   —(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4,                    and R^(i) is hydroxy, C₁₋₇alkyl,                -    or C₁₋₇alkoxy,                -   —(CH₂)_(z)—C(O)NR^(v)R^(vi), wherein z is 0, 1, 2, 3                    or 4, and R^(v) and R^(vi) are independently                -    hydrogen,                -    C₁₋₇alkyl, optionally substituted by one or more                    halo, OH or CN,                -    C₃₋₇cycloalkyl, optionally substituted by one or                    more B,                -    5- or 6-membered heterocyclyl, optionally                    substituted by one or more A, or                -    R^(v) and R^(vi) together with the nitrogen to                    which they are bound form a 5- or 6-membered                    heterocycloalkyl, optionally substituted by one or                    more A,            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a heterocyclyl moiety, optionally                substituted with one or more A, or            -   R^(b) and R^(c) together with the nitrogen to which they                are bound form a 7- to 12-membered spirocyclic                heterocycle, optionally substituted with one or more A;        -   —NR^(d)R^(e), wherein R^(d) and R^(e) are each independently            -   hydrogen,            -   C₁₋₇alkyl,            -   —C(O)C₁₋₇alkyl, optionally substituted with one or more                halo,            -   —C(O)(CH₂)_(m)—O—C₁₋₇alkyl, wherein m is 0, 1, 2, 3, 4,                5 or 6,            -   —C(O)C(O)OC₁₋₇-alkyl,            -   —C(O)CH₂C(O)OC₁₋₇-alkyl,            -   —C(O)R^(vii), wherein R^(vii) is phenyl or 5- to                6-membered heteroaryl,                -   each optionally substituted with one or more E,            -   —C(O)—C₃₋₇cycloalkyl, optionally substituted with one or                more B,            -   —C(O)—R^(viii), wherein R^(viii) is 3- to 7-membered                heterocyclkyl,                -   optionally substituted by one or more A;    -   A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,        C₁₋₇hydroxyalkyl, halo, or CN;    -   B is halo, hydroxy, CN, C₁₋₄alkyl, or C₁₋₄haloalkyl; and    -   E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,        C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl,        -   C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl;            or a pharmaceutically acceptable salt thereof.

Preferred compounds of formula I of present invention are thoseexemplified in examples given below. Particularly preferred are:

-   2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,-   N-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-ethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-fluoro-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2,2-difluoro-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   N-(2-hydroxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   (R,S)—N-(2-hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(3-methoxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopropylmethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-ethyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(4-cyano-thiazol-2-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-pyridin-2-ylmethyl-nicotinamide,-   N-(6-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclobutyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopentyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   (R,S)—N-(2,2-dimethyl-tetrahydro-pyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(1,1-dioxo-hexahydro-1,6-thiopyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-piperidin-4-yl)-nicotinamide,-   N-(1-ethyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(1-isopropyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(1-benzyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(1-ethyl-piperidin-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic    acid,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-{1-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-piperidin-3-yl}-nicotinamide,-   N-{1-[(2-hydroxy-ethylcarbamoyl)-methyl]-piperidin-3-yl}-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(4-fluoro-phenyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   4-benzyloxy-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,-   1-methyl-2′-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-1,2,3,6-tetrahydro-[4,4′]bipyridinyl,-   2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-4-trifluoromethyl-nicotinamide,-   5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   N-isopropyl-5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-furan-3-ylmethyl)-nicotinamide,-   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid isopropyl    ester,-   6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,3,3,3-pentafluoro-propyl)-nicotinamide,-   6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   N-cyclopropylmethyl-6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamide,-   6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide,-   6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   N-cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   N-cyclopropyl-6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   (1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone,-   3-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-oxetan-3-ol,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid    methyl ester,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone,-   {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone,-   {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone,-   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   N-cyclopropylmethyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-isopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   N-isopropyl-6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinamide,-   6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   N-cyclopropylmethyl-6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinamide,-   6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-isopropyl-nicotinamide,-   N-cyclopropyl-6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinamide,-   6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   N-(2-hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-methoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(1,1-dioxo-tetrahydro-thiophen-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(3,3,3-trifluoro-2-hydroxy-propyl)-nicotinamide,-   (4-hydroxy-piperidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   N-(3-hydroxy-2,2-dimethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-isopropoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   (3-hydroxy-azetidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   N-(2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-hydroxy-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(1-hydroxy-cyclopropylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N—((R)-2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N—((S)-2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1S,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1S,2R) and    (1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-hydroxy-1-hydroxymethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N—(S)-tetrahydro-furan-3-yl-nicotinamide,-   N-((1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide    or    N-((1S,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1S,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide    or    N-((1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-acetylamino-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N—((S)-1-hydroxymethyl-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N—((S)-1-hydroxymethyl-3-methyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N—((S)-1-hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N—((R)-1-hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1R,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide    or    N-((1S,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1S,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide    or    N-((1R,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1S,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide    or    N-((1R,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-((1R,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide    or    N-((1S,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-[2-(2-oxo-imidazolidin-1-yl)-ethyl]-nicotinamide,-   N-(3-hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-azetidine-1-carboxylic    acid tert-butyl ester,-   (2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-ethyl)-carbamic    acid tert-butyl ester,-   N-(2,3-dihydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(3-hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(4-hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(5-hydroxy-pentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(6-hydroxy-hexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   (3-hydroxy-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   ((S)-2-hydroxymethyl-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   ((R)-2-hydroxymethyl-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   N-(3-benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,-   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-pyrrolidin-1-yl-methanone,-   (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic    acid methyl ester,-   (cis or    trans)-N-(3-benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic    acid,-   N-(3-methyl-oxetan-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,    butane-1-sulfonic acid    [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,-   cyclopropanesulfonic acid    methyl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-1H-pyrazol-4-yl)-nicotinamide,-   1-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-1,2-dihydro-pyrazol-3-one,-   N-(1-methyl-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   azetidin-1-yl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   (3-methoxy-azetidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiazolidin-3-yl-methanone,-   N-(1-cyano-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-nicotinamide,-   5-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,-   2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-methylsulfanyl-pyridine,-   5-methanesulfinyl-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,-   6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide-   N-isopropyl-6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide-   N-Isopropyl-6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-[3-(2-fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(1-methyl-1H-pyrazol-4-yl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide    or    6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide    or    6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide,-   6-[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,-   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2-dimethyl-propyl)-nicotinamide,-   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-2-methyl-propyl)-nicotinamide,-   6-[3-(4-chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid    methyl ester,-   6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   N-isopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   [6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone,-   6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   (1,1-dioxo-1,6-thiomorpholin-4-yl)-[6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,-   N-cyclopropylmethyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   methyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   ethyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   (2-hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   [6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone,-   6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid,-   (2-hydroxy-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   (2-methoxy-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic    acid methyl ester,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic    acid,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide,-   cyclopropyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy](2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,-   cyclopropylmethyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,-   (1,1-dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide,-   {6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone,-   ethyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-methyl-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic    acid methyl ester,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropyl-nicotinamide,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic    acid,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropylmethyl-nicotinamide,-   {6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1,6-thiomorpholin-4-yl)-methanone,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2,2,2-trifluoro-ethyl)-nicotinamide,-   {6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone,-   {6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone,-   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide,-   6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid    methyl ester,-   N-isopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-(2-hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   [6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone,-   N-ethyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-methyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   [6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone,-   N-(2-hydroxy-ethyl)-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-isopropyl-6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-methyl-ethyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide,-   N-cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,-   N-cyclopropyl-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide    or    6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide,-   N-(2-acetylamino-ethyl)-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-methoxy-ethyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-propyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(1-hydroxy-cyclopropylmethyl)-nicotinamide,-   N-(1,1-dioxo-tetrahydro-1,6-thiophen-3-yl)-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide    or    6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-propyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-propyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2-dimethyl-propyl)-nicotinamide,-   3-({6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyridine-3-carbonyl}-amino)-azetidine-1-carboxylic    acid tert-butyl ester,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide    and    6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide,-   N-(2-acetylamino-ethyl)-6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,-   6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,-   N-isopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-cyclopropylmethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   N-(2-hydroxy-ethyl)-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   N-ethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide,-   cyclopropyl-6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2,2,2-trifluoro-ethyl)-nicotinamide,-   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide,-   ethyl-6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamide,    or    6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-methyl-nicotinamide.

The present compounds of formula I (X═O) and their pharmaceuticallyacceptable salts can be prepared by a process comprising

a) reacting a compound of formula II (R=halo, a=0, 1, 2, or 3):

with ethyl trifluoroacetate in a suitable solvent, such astert-butylmethylether, in the presence of a base, such as sodiummethoxide, to give a compound of formula III:

b) reacting the compound of formula III with hydroxylamine hydrochloridein the presence of a suitable base, such as sodium hydroxide, in asuitable solvent, such as ethanol, to give a compound of formula IV:

c) reacting the compound of formula IV with trifluoroacetic acid, togive a compound of formula V:

d) reacting the compound of formula V with a base, such as BuLi and2,2,6,6-tetramethylpiperidine in a suitable solvent, such as THF,followed by carbon dioxide, to give a compound of formula VI:

e) reacting the compound of formula VI with a base, such astriethylamine, in a suitable solvent, such as THF, followed by reactionwith ethyl chloroformate and a reducing agent, such assodiumborohydride, to give a compound of formula VII:

or alternatively,f) reacting a compound of formula VIII:

with hydroxylamine hydrochloride in a suitable solvent, such as ethanoland water, in the presence of a base, such as aqueous sodium hydroxide,to give a compound of formula IX:

g) reacting the compound of formula IX with a chlorinating agent, suchas N-chlorosuccinimide, in a suitable solvent, such as DMF, to give acompound of formula X:

h1) and then either reacting the compound of formula X with a compoundof formula XI:

in the presence of a suitable base, such as triethylamine, in a suitablesolvent, such as chloroform, or alternativelyh2) reacting the compound of formula X with a compound of formula XII:

in the presence of a suitable base, such as triethylamine, in a suitablesolvent, such as diethylether, or alternativelyh3) reacting the compound of formula X with a compound of formula XIII:

to give a compound of formula XIV:

i) reacting a compound of formula XIVa with a reducing agent, such aslithiumaluminiumhydride, in a suitable solvent, such as THF, to give acompound of formula XV or reacting a compound of formula XIV with ahydrolytic agent, such as NaOH or LiOH, in a suitable solvent, such asTHF, MeOH or EtOH, water to give a compound of formula XIVb followed byreacting a compound of formula XIVb with a reducing agent, such aslithiumaluminiumhydride or ethylchloroformate, in the presence ofsodiumborohydride in a suitable solvent, such as THF or water, to give acompound of formula XV;

j1) reacting compounds of formula VII or XIVa or XIVb with a compoundsof formula XVI:

in the presence of a suitable base, such as sodium hydride, in asuitable solvent, such as THF, or alternativelyj2) reacting compounds of formula VII or XIV with a compounds of formulaXVII:

in the presence of triphenylphosphine and diethylazodicarboxylate, in asuitable solvent, such as THF, to give a compound of formula I-a (X═O):

wherein R¹ to R³ are as described for formula I hereinabove,and, if desired, converting a compound of formula I into apharmaceutically acceptable salt.

The present compounds of formula I (X═NH) and their pharmaceuticallyacceptable salts can be prepared by a process comprising:

k) reacting a compound of formula XV or VII:

with thionyl chloride in a suitable solvent, such as dichloromethane, togive a compound of formula XVIII:

l) reacting a compound of formula XVIII in the presence of a suitablebase, such as KHMDS, with 2-aminopyridine in a suitable solvent, such asTHF, to give a compound of formula I-b (X═NH, R³⁻⁶═H)):

m) reacting a compound of formula XIV:

with phthalimide in the presence of triphenylphosphine anddiethylazodicarboxylate, in a suitable solvent, such as THF to give acompound of formula XIX:

n) reacting the compound of formula XIX with hydrazine, to give acompound of formula XX:

o) reacting the compound of formula XX with methyl 6-chloronicotinate,in the presence of a suitable base, such as N,N-diisopropyl ethyl amine,in a suitable solvent, such as DMSO, under microwave irradiation atelevated temperatures, such as 160° C., to give a compound of formulaI-c′:

In accordance with Schemes 1-5, compounds of formula I can be preparedfollowing standard methods.

on=overnightrt=room temperatureDMF=N,N-dimethylformamideTBTU=O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborateHOBt=N1-hydroxybenzotriazoleDIPEA=N,N-diisopropylethylamineDCM=dichloromethaneDMAP=N,N-dimethylamino-4-pyridineEtOH=ethanolEDAC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochlorideTBD=1,5,7-triazabicyclo[4.4.0]dec-5-eneCDI=1,1′-carbonyldiimidazoleAs mentioned earlier, the compounds of formula I and theirpharmaceutically usable salts possess valuable pharmacologicalproperties. Compounds of the present invention are ligands for GABA Areceptors containing the α5 subunit and are therefore useful in thetherapy where cognition enhancement is required.

The compounds were investigated in accordance with the test givenhereinafter:

Membrane Preparation and Binding Assay

The affinity of compounds at GABA A receptor subtypes was measured bycompetition for [3H]flumazenil (85 Ci/mmol; Roche) binding to HEK293cells expressing rat (stably transfected) or human (transientlytransfected) receptors of composition α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2.

Cell pellets were suspended in Krebs-tris buffer (4.8 mM KCl, 1.2 mMCaCl2, 1.2 mM MgCl₂, 120 mM NaCl, 15 mM Tris; pH 7.5; binding assaybuffer), homogenized by polytron for ca. 20 sec on ice and centrifugedfor 60 min at 4° C. (50000 g; Sorvall, rotor: SM24=20000 rpm). The cellpellets were resuspended in Krebs-tris buffer and homogenized bypolytron for ca. 15 sec on ice. Protein was measured (Bradford method,Bio-Rad) and aliquots of 1 mL were prepared and stored at −80° C.

Radioligand binding assays were carried out in a volume of 200 mL(96-well plates) which contained 100 mL of cell membranes,[3H]flumazenil at a concentration of 1 nM for α1, α2, α3 subunits and0.5 nM for α5 subunits and the test compound in the range of10-10⁻³×10⁻⁶ M. Nonspecific binding was defined by 10⁻⁵ M diazepam andtypically represented less than 5% of the total binding. Assays wereincubated to equilibrium for 1 hour at 4° C. and harvested onto GF/Cuni-filters (Packard) by filtration using a Packard harvester andwashing with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying,filter-retained radioactivity was detected by liquid scintillationcounting. Ki values were calculated using Excel-Fit (Microsoft) and arethe means of two determinations.

The compounds of the accompanying examples were tested in the abovedescribed assay, and the preferred compounds were found to possess a Kivalue for displacement of [³H]flumazenil from α5 subunits of the ratGABA A receptor of 100 nM or less. Most preferred are compounds with aKi (nM)<35. In a preferred embodiment the compounds of the invention arebinding selective for the α5 subunit relative to the α1, α2 and α3subunit.

“h” in hKi means “human” hKi hKi hKi hKi Example GABAAa5 Example GABAAa5Example GABAAa5 Example GABAAa5 1 36.5 14 2.5 27 2.7 40 13.8 2 3.1 155.2 28 2.8 41 9.3 3 31.1 16 3.9 29 3.9 42 13.7 4 60.8 17 7.7 30 13.1 4312.3 5 13.1 18 19.4 31 2.1 44 10.1 6 22.2 19 13.1 32 8 45 8.4 7 14.2 2021.6 33 4.9 46 13.1 8 4.3 21 2.8 34 6.3 47 11.8 9 2.9 22 4.6 35 9.4 4838 10 4.4 23 6.5 36 9.9 49 12.1 11 2 24 35 37 7.3 50 20.2 12 2.2 25 20.238 43.5 51 50.8 13 2.6 26 1.3 39 5 52 16.8 53 23.6 73 20.9 93 1.7 11320.9 54 25.6 74 28.1 94 48.1 114 42.6 55 22.8 75 29.9 95 45.6 115 4.5 5635.1 76 11.7 96 13.4 116 22.3 57 32.1 77 4.6 97 27.4 117 2.1 58 37.8 7840.7 98 7.8 118 1.3 59 55.4 79 68.1 99 8.1 119 0.7 60 38.7 80 44.4 1007.6 120 1.1 61 18.4 81 15.1 101 3.9 121 0.8 62 14.6 82 16.8 102 19.5 1222.9 63 10.7 83 4.7 103 16.2 123 5.4 64 34.4 84 4.5 104 39.5 124 7.5 6524.4 85 9.8 105 1.2 125 2.7 66 1.4 86 3.6 106 1.5 126 4.7 67 47.3 87 4.6107 0.7 127 2.4 68 18.6 88 17.4 108 1.1 128 88.5 69 2.95 89 3 109 0.8129 24.3 70 53.1 90 3.2 110 13 130 30.8 71 80.8 91 2.3 111 10.4 131 3472 19.3 92 41.3 112 4.7 132 28.3 133 41.6 153 65.7 173 5.9 193 2.3 13423.8 154 53.2 174 7.6 194 2.1 135 22.1 155 24 175 3.7 195 1.7 136 57 15629.8 176 7.4 196 0.7 137 19.8 157 26.3 177 6.5 197 11 138 33.3 158 31.7178 29.2 198 6.5 139 16.5 159 27.9 179 9.4 199 2.8 140 57.8 160 87.3 1807.2 200 3.9 141 22.5 161 27.4 181 19.2 201 1.7 142 33.5 162 10.4 18210.1 202 1.6 143 38.4 163 37.3 183 10 203 4.8 144 12.5 164 5.9 184 7.8204 4.4 145 58.9 165 10.6 185 4.5 205 4 146 5.9 166 8.8 186 2.3 206 1.8147 4.1 167 69.3 187 73.4 207 10.9 148 7.1 168 17.8 188 7.7 208 0.7 1494.5 169 15.4 189 41.3 209 2.3 150 5.6 170 19.4 190 1 210 5 151 84.5 17114.9 191 5 211 2.7 152 39.7 172 25.9 192 2.9 212 2 213 1.6 233 32.2 2530.8 273 0.6 214 4.3 234 0.6 254 4.1 274 14.6 215 2.3 235 1.9 255 0.8 2751.1 216 4.5 236 36.7 256 0.8 276 10.1 217 8.4 237 1.1 257 0.5 277 1.5218 2 238 34.9 258 1.3 278 1.6 219 2.2 239 3.6 259 0.7 279 1.3 220 2.6240 13.9 260 0.5 280 1.1 221 4.1 241 16 261 26.5 281 4 222 8.2 242 37.3262 5.2 282 6.8 223 26.1 243 2.9 263 2.4 283 22.3 224 41.9 244 5.1 2642.3 284 0.5 225 20.2 245 3.3 265 27.3 285 1.1 226 2.6 246 1.1 266 4.3286 2 227 48 247 17.7 267 9.3 287 19.2 228 37.1 248 28.1 268 3.3 288 0.4229 47.7 249 3.2 269 6.7 289 0.3 230 1.2 250 3.1 270 0.4 290 0.6 231 28251 0.9 271 3.8 291 1.2 232 1.4 252 1 272 1.1 292 0.4 293 1.2 313 3 33313.1 353 5.5 294 0.3 314 5.6 334 21.2 354 10.7 295 0.4 315 8.1 335 37.6355 4.3 296 4.1 316 36.2 336 40.7 356 13.1 297 0.5 317 3.1 337 9.5 357~20 298 0.6 318 4.8 338 23.3 358 17.8 299 0.5 319 20.2 339 23.1 359 13.1300 1.6 320 6 340 19.4 360 18.9 301 0.3 321 21.4 341 29.2 361 19 302 0.3322 17.7 342 15.1 362 8 303 0.3 323 7.3 343 12.4 363 19.9 304 3.8 32410.6 344 5.6 364 13.6 305 0.6 325 9 345 6.4 365 8 306 0.3 326 27.7 34610.9 366 6.8 307 0.6 327 13.9 347 7.1 367 13.5 308 0.2 328 17.4 348 10.3368 44.9 309 0.6 329 12.9 349 39.9 369 9.3 310 0.4 330 15.1 350 22.9 37021.4 311 0.1 331 17.8 351 55.5 371 14.1 312 11.3 332 22.6 352 8 372 18.5

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example, compounds of formulaI or pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc canbe used as such excipients e.g. for tablets, dragées and hard gelatinecapsules. Suitable excipients for soft gelatine capsules are e.g.vegetable oils, waxes, fats, semisolid and liquid polyols etc. Suitableexcipients for the manufacture of solutions and syrups are e.g. water,polyols, saccharose, invert sugar, glucose etc. Suitable excipients forinjection solutions are e.g. water, alcohols, polyols, glycerol,vegetable oils etc. Suitable excipients for suppositories are e.g.natural or hardened oils, waxes, fats, semi-liquid or liquid polyolsetc.

Moreover, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 0.1 to 1000 mg per person of acompound of general formula I should be appropriate, although the aboveupper limit can also be exceeded when necessary.

The following examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

Example A

Tablets of the following composition can be manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

Example B

Capsules of the following composition can be manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch firstly can be mixed in amixer and then in a comminuting machine. The mixture can be returned tothe mixer; the talc then can be added thereto and mixed thoroughly. Themixture can be filled by machine into hard gelatine capsules.

Example C

Suppositories of the following composition can be manufactured:

mg/supp. Active substance 15 Suppository mass 1285 Total 1300

The suppository mass can melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered activesubstance can be added thereto and stirred until it has dispersedcompletely. The mixture then can be poured into suppository moulds ofsuitable size and left to cool; the suppositories then can be removedfrom the moulds and packed individually in wax paper or metal foil.

The following examples 1-372 are provided for illustration of theinvention. They should not be considered as limiting the scope of theinvention, but merely as being representative thereof.

Example 1 2-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (100 mg,0.53 mmol) in THF (6 mL) was added 2-hydroxypyridine (50 mg, 0.53 mmol)and tributyl phosphine (206 μL, 0.79 mmol) at ambient temperature underan argon atmosphere. After cooling to 0° C.,N,N,N′,N′-tetramethylazodicarboxamide (137 mg, 0.79 mmol) was added. Theresulting orange solution was stirred for 16 h at ambient temperaturefollowed by 2.5 h at 50° C. Then triphenylphosphine (208 mg, 0.79 mmol),2-hydroxypyridine (50 mg, 0.53 mmol) and diethyl azodicarboxylate (127μL, 0.79 mmol) were added and the reaction mixture was stirred for 4 hat 50° C. The reaction mixture was then evaporated. Purification bychromatography (SiO₂, heptane:ethyl acetate=95:5 to 0:100) afforded thetitle compound (36 mg, 25%) as a colourless oil. MS: m/e=267.2 [M+H]⁺.

Example 2 2-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine

To a suspension of sodium hydride (55% dispersion in mineral oil, 48 mg,1.1 mmol) in THF (1.5 mL) was added a solution of(5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) in THF (3mL) at 0° C. and the reaction mixture warmed to room temperature over 30min. Then a solution of 2-fluoro-6-methylpyridine (122 mg, 1.1 mmol) inTHF (3 mL) was added dropwise at 0° C. and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was thenpoured into aqueous sodium chloride (saturated) and the mixture wasextracted with ethyl acetate. The combined organic layers were thenwashed with water and brine and then dried over sodium sulfate, filteredand evaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 4:1) afforded the title compound (135 mg, 48%) whichwas obtained as a yellow oil. MS: m/e=281.1 [M+H]⁺.

Example 3 5-Bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0mmol) in THF (12 mL) was added 2-hydroxy-5-bromopyridine (191 mg, 1.1mmol) and triphenylphosphine (393 mg, 1.5 mmol) at ambient temperatureunder an argon atmosphere. Then diethyl azodicarboxylate (233 μL, 1.5mmol) was added and the reaction mixture was stirred for 3 h at roomtemperature. Concentration and purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (144 mg,42%) as a colourless gum. MS: m/e=345.0/347.1 [M+H]⁺.

Example 42-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-trifluoromethyl-pyridine

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (95 mg, 0.50mmol) in THF (6 mL) was added 2-hydroxy-5-trifluoromethylpyridine (90mg, 0.55 mmol) and triphenylphosphine (197 mg, 0.75 mmol) at ambienttemperature under an argon atmosphere. Then diethyl azodicarboxylate(120 μL, 0.75 mmol) was added and the reaction mixture was stirred for2.5 h at 50° C. Concentration and purification by chromatography (SiO₂,heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (86 mg,51%) as a colourless oil. MS: m/e=335.3 [M+H]⁺.

Example 5 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinonitrile

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (220 mg,1.16 mmol) in THF (2 mL) was added sodium hydride (55% dispersion inmineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambienttemperature 6-chloronicotinonitrile (161 mg, 1.16 mmol) was added andthe reaction mixture was stirred for 5 h at ambient temperature. It wasdiluted with ethyl acetate (10 mL), washed with aqueous citric acid(10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10mL). The combined aqueous layers were extracted with ethyl acetate (10mL). After drying over sodium sulfate and concentration purification bychromatography (SiO₂, heptane:ethyl acetate=90:10 to 60:40) afforded thetitle compound (307 mg, 91%) as a white solid. MS: m/e=292.1 [M+H]⁺.

Example 6 2-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-nitro-pyridine

As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(200 mg, 1.06 mmol) was converted using 2-hydroxy-5-nitro-pyridineinstead of 2-hydroxy-5-trifluoromethylpyridine to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=80:0:20 to 50:30:20, 122mg, 37%) which was obtained as a white solid. MS: m/e=312.2 [M+H]⁺.

Example 7 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester

As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(200 mg, 1.06 mmol) was converted using methyl 6-chloronicotinateinstead of 6-chloronicotinonitrile to the title compound (SiO₂,heptane:ethyl acetate=100:0 to 70:30, 191 mg, 42%) which was obtained asa colourless oil. MS: m/e=325.3 [M+H]⁺.

Example 8N-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide a)6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid methyl ester (3.89 g, 120 mmol) in ethanol (40 mL) was addedaqueous sodium hydroxide (1 M, 36.0 mL, 36.0 mmol). After heating atreflux for 2 h it was cooled to ambient temperature and concentrated.Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed bywashing with tert-butylmethylether (100 mL). The aqueous phase wasacidified with aqueous hydrogen chloride (conc.) to pH=1 and extractedwith tert-butylmethylether (100 mL). The organic layer was washed withwater (50 mL) and aqueous sodium chloride (saturated, 50 mL). Dryingover sodium sulfate and concentration afforded the title compound (1.68g, 45%) as an off white solid. MS: m/e=309.3 [M−H]⁻.

b) N-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (100 mg, 0.32 mmol) in DMF (2 mL) were added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) andmethylamine (1 M solution in MeOH, 354 μL, 0.35 mmol). The resultingreaction mixture was stirred overnight at room temperature.Concentration and purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (40 mg, 33%) as an offwhite solid. MS: m/e=324.4 [M+H]⁺.

Example 9N-Ethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using ethylamine instead of methylamine, to thetitle compound (90 mg, 83%) which was obtained as a white solid. MS:m/e=338.4 [M+H]⁺.

Example 10N-(2-Fluoro-ethyl)-6-(5-methyl-3-phenyl-_(isoxazol)-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 2-fluoroethylamine hydrochloride instead ofmethylamine, to the title compound (109 mg, 95%) which was obtained as awhite solid. MS: m/e=356.3 [M+H]⁺.

Example 11N-(2,2-Difluoro-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 2,2-difluoroethylamine instead ofmethylamine, to the title compound (96 mg, 80%) which was obtained as anoff white solid. MS: m/e=374.1 [M+H]⁺.

Example 126-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (200 mg, 0.64 mmol) in DMF (2 mL) were added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and2,2,2-trifluoroethylamine 77 μL, 0.77 mmol). The resulting reactionmixture was stirred for 12 h at ambient temperature. After dilution withethyl acetate (20 mL) it was washed with water (20 mL) and aqueoussodium carbonate (saturated, 40 mL). The organic layer was dried oversodium sulfate and concentrated. Purification by chromatography (SiO₂,heptane:ethyl acetate=80:20 to 20:80) afforded the title compound (213mg, 84%) as a white solid. MS: m/e=392.2 [M+H]⁺.

Example 13N-(2-Hydroxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using ethanolamine instead of methylamine, to thetitle compound (92 mg, 81%) which was obtained as a white solid. MS:m/e=354.4 [M+H]⁺.

Example 14(R,S)—N-(2-Hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using (R,S)-1-amino-2-propanol instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate:methanol=50:50:0 to 0:95:5, 142 mg, 60%) which was obtained as awhite solid. MS: m/e=368.1 [M+H]⁺.

Example 15N-(3-Methoxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (100 mg, 0.32 mmol) in DMF (2 mL) were added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and3-methoxypropylamine (36 μL, 0.35 mmol). The resulting reaction mixturewas stirred overnight at room temperature. Concentration andpurification by preparative HPLC on reversed phase eluting withacetonitrile/water [0.1% aq NH₃ (25%)] afforded the title compound (101mg, 82%) which was obtained as a white solid. MS: m/e=382.5 [M+H]⁺.

Example 16N-Cyclopropylmethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50mmol) was converted using aminomethylcyclopropane instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate=80:20 to 50:50, 142 mg, 78%) which was obtained as a white foam.MS: m/e=364.3 [M+H]⁺.

Example 17N-(2-Ethyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 2-ethylbutylamine instead of methylamine, tothe title compound (121 mg, 95%) which was obtained as an off whitesolid. MS: m/e=394.4 [M+H]⁺.

Example 18(R,S)6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(3-oxo-isoxazolidin-5-ylmethyl)-nicotinamide

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (200 mg, 0.64 mmol) in DMF (2 mL) was added1,1′-carbonyl-diimidazole (115 mg, 0.71 mmol) and the reaction mixturewas stirred for 0.5 h at 80° C. After cooling to ambient temperature5-aminomethyl-isoxazolidin-3-one (82 mg, 0.71 mmol) was added andstirring was continued for 1 h at this temperature and for 2 h at 80° C.It was diluted with ethyl acetate (10 mL) and washed with water (10 mL)and aqueous sodium chloride (saturated, 10 mL). The organic layer wasdried over sodium sulfate and concentrated. Purification bychromatography (SiO₂, heptane:ethyl acetate:methanol=40:60:0 to 0:90:10)afforded the title compound (13 mg, 5%) as a white solid. MS: m/e=409.3[M+H]⁺.

Example 19N-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 18,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-methylamine instead ofaminomethyl-isoxazolidin-3-one to the title compound (SiO₂,heptane:ethyl acetate=90:10 to 40:60, 97 mg, 34%) which was obtained asa light brown oil. MS: m/e=432.3 [M+H]⁺.

Example 20N-(5-Cyclopropyl-1H-pyrazol-3-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 18,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using (5-cyclopropyl-1H-pyrazol-3-yl)-methylamineinstead of aminomethyl-isoxazolidin-3-one to the title compound (SiO₂,heptane:ethyl acetate:methanol=30:70:0 to 0:95:5, 97 mg, 35%) which wasobtained as a colourless oil. MS: m/e=430.2 [M+H]⁺.

Example 21N-(4-Cyano-thiazol-2-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 18,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using 2-aminomethyl-thiazole-4-carbonitrile insteadof aminomethyl-isoxazolidin-3-one to the title compound (SiO₂,heptane:ethyl acetate=90:10 to 40:60, 188 mg, 68%) which was obtained asa white solid. MS: m/e=432.3 [M+H]⁺.

Example 226-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-pyridin-2-ylmethyl-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using 2-(aminomethyl)pyridine instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate:methanol=50:50:0 to 0:95:5, 191 mg, 74%) which was obtained as awhite solid. MS: m/e=401.2 [M+H]⁺.

Example 23N-(6-Methyl-3-oxo-2,3-dihydro-pyridazin-4-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 18,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using 4-aminomethyl-6-methyl-2H-pyridazin-3-oneinstead of aminomethyl-isoxazolidin-3-one to the title compound (SiO₂,heptane:ethyl acetate:methanol=20:80:0 to 0:90:10, 231 mg, 83%) whichwas obtained as a white solid. MS: m/e=432.3 [M+H]⁺.

Example 24{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-aceticacid tert-butyl ester

As described for example 15,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using glycine tert-butylester hydrochloride insteadof 3-methoxypropylamine, to the title compound (111 mg, 81%) which wasobtained as an off white foam. MS: m/e=424.3 [M+H]⁺.

Example 252-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-propionicacid ethyl ester

As described for example 15,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using DL-alanine ethylester hydrochloride insteadof 3-methoxypropylamine, to the title compound (23 mg, 17%) which wasobtained as a light yellow gum. MS: m/e=410.1 [M+H]⁺.

Example 26N-Isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using isopropylamine (1 M in DMF) instead ofmethylamine, to the title compound (110 mg, 97%) which was obtained asan off white solid. MS: m/e=352.5 [M+H]⁺.

Example 27N-Cyclopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using cyclopropylamine instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate=80:20 to 20:80, 148 mg, 68%) which was obtained as a whitesolid. MS: m/e=350.2 [M+H]⁺.

Example 28N-Cyclobutyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using cyclobutylamine (1 M in DMF) instead ofmethylamine, to the title compound (66 mg, 56%) which was obtained as awhite solid. MS: m/e=364.4 [M+H]⁺.

Example 29N-Cyclopentyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using cyclopentylamine (1 M in DMF) instead ofmethylamine, to the title compound (98 mg, 81%) which was obtained as awhite solid. MS: m/e=378.4 [M+H]⁺.

Example 30N-Cyclohexyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using cyclohexylamine instead of methylamine, tothe title compound (126 mg, 100%) which was obtained as a white solid.MS: m/e=392.3 [M+H]⁺.

Example 316-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate=80:20 to 20:80, 231 mg, 91%) which was obtained as a whitesolid. MS: m/e=394.1 [M+H]⁺.

Example 32(R,S)—N-(2,2-Dimethyl-tetrahydro-pyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using (R,S)-2,2-dimethyl-4-aminotetrahydropyraninstead of 2,2,2-trifluoroethylamine to the title compound (SiO₂,heptane:ethyl acetate=70:30 to 30:70, 140 mg, 52%) which was obtained asa colourless solid. MS: m/e=422.2 [M+H]⁺.

Example 33N-(1,1-Dioxo-hexahydro-1,6-thiopyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 18,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using 4-amino-tetrahydro-thiopyran 1,1-dioxideinstead of aminomethyl-isoxazolidin-3-one to the title compound (164 mg,58%) which was obtained as a white solid. MS: m/e=442.2 [M+H]⁺.

Example 346-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-piperidin-4-yl)-nicotinamide

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (100 mg, 0.32 mmol) in DMF (2 mL) were added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and1-methylpiperidin-4-amine (41 mg, 0.35 mmol). The resulting reactionmixture was stirred overnight at room temperature. Concentration andpurification by preparative HPLC on reversed phase eluting withacetonitrile/water [0.1% aq NH₃ (25%)]. Then the residue was partitionedwith ethyl acetate and water, the organic extract was washed withaqueous sodium hydrogen carbonate (saturated) dried over sodium sulfateand concentrated to afford the title compound (94 mg, 72%) which wasobtained as a white solid. MS: m/e=407.5 [M+H]⁺.

Example 35N-(1-Ethyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 34,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 1-ethylpiperidin-4-amine instead of1-methylpiperidin-4-amine, to the title compound (99 mg, 73%) which wasobtained as an off white solid. MS: m/e=421.1 [M+H]⁺.

Example 36N-(1-Isopropyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 34,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using N-isopropyl-4-aminopiperidine instead of1-methylpiperidin-4-amine, to the title compound (110 mg, 73%) which wasobtained as a white foam. MS: m/e=435.4 [M+H]⁺.

Example 37N-(1-Benzyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 34,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 4-amino-1-benzylpiperidine instead of1-methylpiperidin-4-amine, to the title compound (120 mg, 77%) which wasobtained as an off white foam. MS: m/e=483.3 [M+H]⁺.

Example 383-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

As described for example 34,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using (+/−)-3-amino-1-N-Boc-piperidine instead of1-methylpiperidin-4-amine, to the title compound (96 mg, 61%) which wasobtained as a white foam. MS: m/e=493.3 [M+H]⁺.

Example 39N-(1-Ethyl-piperidin-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 3-amino-N-ethylpiperidine (1 M in DMF)instead of methylamine, to the title compound (64 mg, 95%) which wasobtained as an off white foam. MS: m/e=421.3 [M+H]⁺.

Example 40(3-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid ethyl ester

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (500 mg, 1.6 mmol) in DMF (10 mL) were added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and(3-amino-piperidin-1-yl)-acetic acid ethyl ester hydrochloride (459 mg,1.8 mmol). The resulting reaction mixture was stirred overnight at roomtemperature. Concentration and purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 1:1 and thendichloromethane:methanol=9:1) afforded the title compound (622 mg, 81%)as a light brown gum. MS: m/e=479.1 [M+H]⁺.

Example 41(3-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid

To a solution of(3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid ethyl ester (538 mg, 1.1 mmol) in THF (5 mL) was added a solutionof lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) andmethanol (1 mL) added and the resulting mixture stirred at roomtemperature overnight. The mixture was acidified to pH 4 with HCl (25%,3 drops) and methanol (2 drops) added. A gum began to form and themixture was cooled at 0° C. for 1.5 h and then the aqueous layerdecanted off. Trituration with diethylether and hexane afforded thetitle compound (420 mg, 83%) which was obtained as an off white solid.MS: m/e=449.0 [M−H]⁻.

Example 42N-(1-Ethylcarbamoylmethyl-piperidin-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,(3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid (70 mg, 0.16 mmol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted,using ethylamine (1 M in DMF) instead of methylamine, to the titlecompound (47 mg, 63%) which was obtained as an off white solid aftertrituration with water. MS: m/e=478.3 [M+H]⁺.

Example 43N-(1-Cyclopropylcarbamoylmethyl-piperidin-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 42,(3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid (70 mg, 0.16 mmol) was converted, using cyclopropylamine instead ofmethylamine, to the title compound (52 mg, 63%) which was obtained as awhite solid. MS: m/e=490.5 [M+H]⁺.

Example 446-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-{1-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-piperidin-3-yl}-nicotinamide

As described for example 42,(3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid (70 mg, 0.16 mmol) was converted, using 2,2,2-trifluoroethylamineinstead of methylamine, to the title compound (51 mg, 62%) which wasobtained as an off white solid. MS: m/e=532.0 [M+H]⁺.

Example 45N-{1-[(2-Hydroxy-ethylcarbamoyl)-methyl]-piperidin-3-yl}-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 42,(3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid (70 mg, 0.16 mmol) was converted, using ethanolamine instead ofmethylamine, to the title compound (52 mg, 67%) which was obtained as anoff white solid. MS: m/e=494.3 [M+H]⁺.

Example 466-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-{1-[(tetrahydro-pyran-4-ylcarbamoyl)-methyl]-piperidin-3-yl}-nicotinamide

As described for example 42,(3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid (70 mg, 0.16 mmol) was converted, using 4-aminotetrahydropyraninstead of methylamine, to the title compound (61 mg, 74%) which wasobtained as an off white solid. MS: m/e=534.2 [M+H]⁺.

Example 47N-tert-Butyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 15,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using tert-butylamine instead of3-methoxypropylamine, to the title compound (89 mg, 76%) which wasobtained as an off white solid. MS: m/e=366.3 [M+H]′.

Example 486-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-phenyl-nicotinamide

As described for example 15,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using aniline instead of 3-methoxypropylamine, tothe title compound (87 mg, 70%) which was obtained as an off whitesolid. MS: m/e=386.4[M+H]⁺.

Example 49N-(4-Fluoro-phenyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 4-fluoroaniline (1 M in DMF) instead ofmethylamine, to the title compound (109 mg, 84%) which was obtained as awhite solid. MS: m/e=404.4 [M+H]⁺.

Example 50N-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

To a solution of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide(200 mg, 0.51 mmol) in THF (2 mL) was added at 0° C. potassiumbis(trimethylsilyl)amide (0.91 M in THF, 614 μL, 0.56 mmol) over aperiod of 2 min. After stirring for 0.5 h at this temperatureiodomethane (41 μL, 0.66 mmol) was added and the resulting suspensionwas stirred for 2 h at ambient temperature. Concentration andpurification by chromatography (SiO₂, heptane:ethyl acetate=50:50 to0:100) afforded the title compound (91 mg, 44%) as a white foam. MS:m/e=408.5 [M+H]⁺.

Example 51[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-piperidin-1-yl-methanone

As described for example 15,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using piperidine instead of 3-methoxypropylamine,to the title compound (91 mg, 75%) which was obtained as a yellow gum.MS: m/e=378.5 [M+H]⁺.

Example 52(4,4-Difluoro-piperidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 4,4-difluoropiperidine hydrochloride (1 M inDMF) instead of methylamine, to the title compound (131 mg, 98%) whichwas obtained as a light yellow gum. MS: m/e=414.4 [M+H]⁺.

Example 53[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted using morpholine instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate=80:20 to 20:80, 165 mg, 67%) which was obtained as a whitesolid. MS: m/e=380.3 [M+H]⁺.

Example 54[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (450 mg, 1.45mmol) was converted using thiomorpholine instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate=80:20 to 20:80, 560 mg, 97%) which was obtained as a whitesolid. MS: m/e=396.1 [M+H]⁺.

Example 55(1,1-Dioxo-1,6-thiomorpholin-4-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

To solution of[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone(423 mg, 1.07 mmol) in a mixture of dichloromethane (4.5 mL), methanol(4.5 mL) and water (65 μL) was added potassium monopersulfate triplesalt (1.32 g, 2.14 mmol) and the reaction mixture was heated at refluxfor 8 h. After cooling it was poured onto aqueous sodium bisulfite (38%,10 mL) and stirred for 45 min at ambient temperature. Extraction withdichloromethane (50 mL) was followed by washing the organic layers withaqueous sodium carbonate (50 mL). Drying over sodium sulfate,concentration and purification of the residue by chromatography (SiO₂,ethyl acetate:dichloromethane=80:20 to 20:80) afforded the titlecompound (15 mg, 3%) as a colourless oil. MS: m/e=427.5 [M+H]⁺

Example 564-Benzyloxy-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine

As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(95 mg, 0.50 mmol) was converted using 4-benzyloxy-2(1H)-pyridoneinstead of 2-hydroxy-5-trifluoromethylpyridine to the title compound(SiO₂, heptane:ethyl acetate=95:5 to 0:100, 52 mg, 28%) which wasobtained as a colourless oil. MS: m/e=373.1 [M+H]⁺.

Example 571-Methyl-2′-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-1,2,3,6-tetrahydro-[4,4′]bipyridinyl

As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(135 mg, 0.72 mmol) was converted using1′-methyl-1′,2′,3′,6′-tetrahydro-1H-[4,4′]bipyridinyl-2-one instead of2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO₂,heptane:ethyl acetate:methanol=95:5:0 to 0:80:20, 45 mg, 17%) which wasobtained as a yellow oil. MS: m/e=362.3 [M+H]⁺.

Example 582-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-isonicotinamidea) 2-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid methylester

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.5 g, 8.0mmol) in THF (79 mL) was added 2-hydroxy-isonicotinic acid methyl ester(1.8 g, 12.0 mmol) and triphenylphosphine (2.8 g, 11 mmol) at roomtemperature under an argon atmosphere. Then diethyl azodicarboxylate(1.64 mL, 11 mmol) was added and the reaction mixture was stirredovernight at room temperature. Then 2-hydroxy-isonicotinic acid methylester (0.2 g, 0.17 mmol) was added and the resulting mixture stirred atroom temperature for 1 h and then heated at 60° C. for 1 h. Aftercooling to room temperature, concentration and purification bychromatography (SiO₂, heptane:ethyl acetate=100:0 to 1:1) afforded thetitle compound (0.99 g, 38%) as a light yellow solid. MS: m/e=325.1[M+H]⁺.

b) 2-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid

To a suspension of2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid methylester (759 mg, 2.3 mmol) in THF (6.3 mL) was added a solution of lithiumhydroxide monohydrate (196 mg, 4.7 mmol) in water (6.3 mL) and methanol(1.4 mL) added and the resulting mixture stirred at room temperature for2 h. The mixture was acidified to pH 4 with HCl (25%, 3 drops and theresulting precipitate filtered off and dried to afford the titlecompound (641 mg, 88%) which was obtained as a white solid. MS:m/e=309.5 [M−H]⁻.

c)2-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide

As described for example 8b,2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid (78 mg, 0.3mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid, was converted, using 2,2,2-trifluoroethylamine instead ofmethylamine, to the title compound (49 mg, 51%) which was obtained as awhite solid. MS: m/e=392.3 [M+H]⁺.

Example 592-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-isonicotinamide

As described for example 58c,2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid (78 mg, 0.3mmol) was converted, using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine, to the title compound (61 mg, 62%) which wasobtained as a white solid. MS: m/e=394.3 [M+H]⁺.

Example 602-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

To a solution of5-bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide(150 mg, 0.37 mmol) in methanol (3 mL) and THF (3 mL) was added under anargon atmosphere palladium on charcoal (10%, 20 mg) and ammonium formate(70 mg, 1.12 mmol). The reaction mixture was stirred for 6 h at ambienttemperature. Filtration over Hyflo® and washing with THF afforded thetitle compound (29 mg, 20%) which was obtained as a light brownsemi-solid. MS: m/e=408.3 [M+H]⁺.

Example 616-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinicacid a)6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinicacid methyl ester

As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(3.47 g, 18.4 mmol) was converted using methyl6-chloro-4-(trifluoromethyl)nicotinate instead of6-chloronicotinonitrile to the title compound which was used directly inthe next transformation without further purification.

b)6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinicacid

As described for example 8a,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinicacid methyl ester (example 61a) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl esterwas converted to the title compound (3.61 g, 52%) which was obtained asa white solid. MS: m/e=377.4 [M−H]⁻.

Example 62N-Isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinicacid (200 mg, 0.53 mmol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was convertedusing isopropylamine instead of 2,2,2-trifluoroethylamine to the titlecompound (SiO₂, ethyl acetate:dichloromethane=100:0 to 50:50, 60 mg,27%) which was obtained as an off white solid. MS: m/e=420.1 [M+H]⁺.

Example 636-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-4-trifluoromethyl-nicotinamide

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinicacid (200 mg, 0.53 mmol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was convertedusing 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine to thetitle compound (SiO₂, ethyl acetate:dichloromethane=50:50 to 100:0, 109mg, 45%) which was obtained as a white solid. MS: m/e=462.2 [M+H]⁺.

Example 64 5-Bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid methyl ester

As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(3.60 mg, 19.0 mmol) was converted using methyl5-bromo-6-chloronicotinate instead of 6-chloronicotinonitrile to thetitle compound (SiO₂, heptane:ethyl acetate=90:10 to 60:40, 2.83 g, 37%)which was obtained as a white solid. MS: m/e=403.3/405.2 [M+H]′.

Example 655-Bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamidea) 5-Bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid

As described for example 8a,5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (2.71 g, 6.49 mmol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl esterwas converted to the title compound (2.55 g, 99%) which was obtained asa white solid. MS: m/e=386.9/389.0 [M−H]⁻.

b)5-Bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 31,5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (2.28g, 5.86 mmol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was convertedto the title compound (2.47 g, 89%) which was obtained as a white solid.MS: m/e=471.9/473.9 [M+H]⁺.

Example 665-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

To a suspension of5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide(200 mg, 0.42 mmol) in 1,2-dimethoxyethane (1 mL) was addedtrimethylboroxine (88 μL, 0.64 mmol), aqueous sodium carbonate (1 M,0.64 mL, 0.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (49 mg,0.04 mmol). The reaction mixture was then irradiated in the microwavefor 20 min at 140° C. under an argon atmosphere. It was diluted withethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL).The aqueous layers were extracted with ethyl acetate (10 mL) and thecombined organic layers were dried over sodium sulfate. Trituration fromtert-butylmethylether afforded the title compound (87 mg, 50%) which wasobtained as a white solid. MS: m/e=408.4 [M+H]+

Example 675-Bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamidea) 5-Bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid ethyl ester

As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(402 mg, 2.12 mmol) was converted using5-bromo-6-hydroxy-2-methyl-nicotinic acid ethyl ester instead of2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO₂,heptane:ethyl acetate=100:0 to 50:50, 700 mg, 76%) which was obtained asa colourless oil. MS: m/e=431.1/433.2 [M+H]⁺.

b) 5-Bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid

As described for example 8a,5-bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid ethyl ester (650 mg, 1.51 mmol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl esterwas converted to the title compound (542 mg, 89%) which was obtained asa white solid. MS: m/e=401.3/403.4 [M−H]⁻.

c)5-Bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 31,5-bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (488 mg, 1.21 mmol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was convertedto the title compound (450 mg, 76%) which was obtained as a light brownsolid. MS: m/e=486.3/488.2 [M+H]⁺.

Example 685-Bromo-N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (240mg, 0.6 mmol), instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, wasconverted, using isopropylamine instead of methylamine, to the titlecompound (229 mg, 86%) which was obtained as an off white foam. MS:m/e=430.3/432.2 [M+H]⁺.

Example 69N-Isopropyl-5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 66,5-bromo-N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(150 mg, 0.35 mmol), instead of5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamidewas converted to the title compound (73 mg, 52%) which was obtained asan off white gum. MS: m/e=366.0 [M+H]⁺.

Example 70N-Isopropyl-N-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 50,N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide (200mg, 0.6 mmol), instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,was converted to the title compound (69 mg, 33%) which was obtained as acolourless gum. MS: m/e=366.3 [M+H]⁺.

Example 71(3,3-Dimethyl-morpholin-4-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 12,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (124 mg, 0.40mmol) was converted using 3,3-dimethyl-morpholine instead of2,2,2-trifluoroethylamine to the title compound (SiO₂, heptane:ethylacetate=80:20 to 30:70, 41 mg, 25%) which was obtained as a light brownoil. MS: m/e=408.1 [M+H]⁺.

Example 72 2-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid ethyl ester

As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol(313 mg, 1.66 mmol) was converted using 6-hydroxy-2-methyl-nicotinicacid ethyl ester instead of 2-hydroxy-5-trifluoromethylpyridine to thetitle compound (SiO₂, heptane:ethyl acetate=60:40 to 10:90, 322 mg, 55%)which was obtained as a colourless oil. MS: m/e=353.2 [M+H]⁺.

Example 736-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carbonitrile

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0mmol) and 6-chloropyridine-2-carbonitrile (150 mg, 1.0 mmol) in toluene(10 mL) was added sodium hydride (55% dispersion in mineral oil, 100 mg,2.0 mmol) and the mixture heated at 50° C. for 6 h. Then 18-crown-6 (18mg) was added and the mixture heated at 100° C. overnight. The mixturewas then diluted with ethyl acetate and washed with water. The aqueouslayers were extracted with ethyl acetate (10 mL) and the combinedorganic layers were dried over sodium sulfate. Purification bychromatography (SiO₂, heptane:ethyl acetate=7:3) afforded the titlecompound (70 mg, 24%) as a white solid after trituration withdiisopropylether. MS: m/e=292.0 [M+H]⁺.

Example 743-[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-oxetan-3-ol

A solution of5-bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine (100 mg,0.29 mmol) THF (3 mL) was treated with n-butyl lithium (1.6 M inhexanes, 0.18 mL, 0.29 mmol) at −75° C. Then a solution of 3-oxetanone(22.0 mg, 0.29 mmol) in THF (1 mL) was added and the mixture was stirredfor 10 min. Methanol was then added and the mixture was allowed to warmto room temperature. Purification by chromatography (SiO₂,ethylacetate/heptane 2:8 to 1:1) afforded the title compound (65 mg,66%) as a white solid. MS: m/e=339.1 [M+H]⁺.

Example 75(5,6-Dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 40,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)-pyrazine hydrochloride insteadof (3-amino-piperidin-1-yl)-acetic acid ethyl ester hydrochloride, tothe title compound (121 mg, 86%) which was obtained as a white foam. MS:m/e=417.4 [M+H]⁺.

Example 766-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-3-ylmethyl)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using (tetrahydro-2-H-pyran-3-yl)methanaminehydrochloride instead of methylamine, to the title compound (33 mg, 25%)which was obtained as a white solid after crystallisation from ethylacetate:hexane. MS: m/e=408.4 [M+H]⁺.

Example 776-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-furan-3-ylmethyl)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using (tetrahydrofuran-3-yl)methanaminehydrochloride instead of methylamine, to the title compound (103 mg,81%) which was obtained as a white solid. MS: m/e=394.3 [M+H]⁺.

Example 78(6,7-Dihydro-5H-pyrazolo[1,5-a]pyrimidin-4-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 4,5,6,7-tetrahydropyrazolo(1,5-a)-pyrimidinehydrochloride instead of methylamine, to the title compound (41 mg, 31%)which was obtained as a light yellow solid after crystallisation fromethyl acetate:hexane. MS: m/e=416.4 [M+H]′.

Example 79N-Isochroman-4-yl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using rac-3,4-dihydro-1H-isochromen-4-aminehydrochloride instead of methylamine, to the title compound (136 mg,96%) which was obtained as an off white solid. MS: m/e=442.3 [M+H]⁺.

Example 80N-(3-Isopropyl-isoxazol-5-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 5-aminomethyl-3-isopropylisoxazole TFAinstead of methylamine, to the title compound (112 mg, 81%) which wasobtained as a colourless gum. MS: m/e=433.3 [M+H]⁺.

Example 81[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 2-oxa-6-aza-spiro[3.3]heptane oxalate insteadof methylamine, to the title compound (96 mg, 76%) which was obtained asan off white solid. MS: m/e=392.4 [M+H]⁺.

Example 82[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone

As described for example 15,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (33 mg, 0.1mmol) was converted, using 6-oxa-1-aza-spiro[3.3]heptane instead of3-methoxypropylamine, to the title compound (15 mg, 35%) which wasobtained as a colourless gum. MS: m/e=392.3 [M+H]⁺.

Example 83 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acidisopropyl ester

A solution of N,N-dicyclohexylcarbodiimide (258 mg, 1.25 mmol) and4-dimethylaminopyridine (12 mg, 0.10 mmol) in dichloromethane (4 mL) wasadded dropwise to a solution of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0mmol) and 2-propanol (0.06 g, 1.0 mmol) in dichloromethane (4 mL) atroom temperature. After 15 h, the mixture was filtered and the filtratewas concentrated and purified by chromatography (SiO₂, heptane:ethylacetate 100:0 to 8:2) to give the title compound (270 mg, 77%) as acolourless oil. MS: m/e=353.1 [M+H]⁺.

Example 846-[3-(2-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamidea) 2-Fluoro-benzaldehyde oxime

To a suspension of 2-fluorobenzaldehyde (63.3 g, 495 mmol) andhydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) andwater (69 mL) was added ice (205 g). Then an aqueous solution of sodiumhydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 minperiod (temperature rises from −8° C. to +7° C.) whereupon most of thesolid dissolves. After 1 h stirring at room temperature the resultingmixture was then acidified with HCl (5 N). The mixture was thenextracted with dichloromethane to afford the title compound (66.8 g,97%) which was obtained as a light yellow solid. MS m/e (EI): 139.0 [M].

b) (E)- and/or (Z)—N-Hydroxy-2-fluoro-benzenecarboximidoyl chloride

To a solution of (E)- and/or (Z)-2-fluoro-benzaldehyde oxime (66.8 g,480 mmol) in DMF (334 mL) was added N-chlorosuccinimide (29.4 g, 211mmol) portionwise and after 10 min, keeping the temperature below 50°C., N-chlorosuccinimide (44.1 g, 317 mmol) was added portionwise. Thereaction mixture was stirred at room temperature for 2 h and thenextracted with tert-butyl methyl ether to afford the title compound(91.9 g, 91%) which was obtained as a yellow oil. 1H-NMR (CDCl₃):7.10-7.25 (m, 2H), 7.40-7.50 (m, 1H), 7.64-7.70 (m, 3H), 8.99 (s, 1H).

c) 3-(2-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester

To a solution of ethyl 2-butynoate (65.5 mL, 562 mmol) and triethylamine(80.7 mL, 576 mmol) in ethanol (600 mL) was added, at 0-4° C. over 2 h,500 mL of a solution of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride (83.3 g 480 mmol)in ethanol (900 mL). Ethyl 2-butynoate (44.6 ml, 383 mmol) in ethanol(125 mL) was added at 0° C., then the remaining 400 ml of the (E)-and/or (Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride solutionwere added over a 1 h period. The resulting mixture was then stirred for48 h at room temperature and evaporated. The mixture was then pouredonto HCl (1.2 L), and extracted with tert-butyl methyl ether. Thecombined organic layers were then washed with water and brine, driedover sodium sulfate and evaporated. Purification by chromatography(SiO₂, heptane:ethyl acetate=100:0 to 9:1) afforded the title product(73.6 g, 62%) which was obtained as a yellow oil, MS: m/e=250.1 [M+H]⁺.

d) [3-(2-Fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

To a solution of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylicacid ethyl ester (73.6 g, 295 mmol) in THF (977 mL) was addedportionwise lithiumaluminiumhydride (6.48 g, 162 mmol) over 20 min, at0° C., and the reaction mixture was stirred at room temperature for 2.5h. The mixture was then cooled to 0° C. and water (7.5 mL) addedfollowed by sodium hydroxide (15% solution, 7.5 mL) and then again withwater (21 mL). The precipitate was then filtered off and washed withTHF. The combined washings and filtrate were then evaporated.Purification by chromatography (SiO₂, heptane:ethyl acetate=75:25)afforded the title compound (34.7 g, 57%) which was obtained as a lightyellow oil. MS: m/e=208.0 [M+H]⁺.

e) 6-[3-(2-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester

To a suspension of sodium hydride (55% dispersion in mineral oil, 1.16g, 26.5 mmol) in THF (30 mL) was added a solution of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.0 g, 24.1 mmol)in THF (60 mL) at 0° C. and the reaction mixture warmed to roomtemperature over 30 min. Then a solution of methyl 6-chloronicotinate(4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was then poured into aqueous sodium chloride (saturated) and themixture was extracted with ethyl acetate. The combined organic layerswere then washed with water and brine and then dried over sodiumsulfate, filtered and evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=4:1 to 2:1) afforded the title compound (4.0 g,49%) which was obtained as a white solid. MS: m/e=343.0 [M+H]⁺.

f)6-[3-(2-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 1.17 mL, 2.3 mmol) wasadded dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine(188 μL, 2.3 mmol) in dioxane (15 mL) and the resulting mixture wasstirred at room temperature for 1.5 h. Then6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.58 mmol) was added. The resulting mixture wasthen heated at 85° C. for 2 h and then cooled to room temperature andthen poured into water and extracted with ethyl acetate which was thenwashed with brine, dried over sodium sulfate and evaporated.Purification by chromatography (SiO₂, heptane:ethyl acetate=2:1 to 1:1)afforded the title compound (210 mg, 88%) which was obtained as acolourless oil. MS: m/e=410.4 [M+H]⁺.

Example 856-[3-(2-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,3,3,3-pentafluoro-propyl)-nicotinamide

As described for example 84f,6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (100 mg, 0.292 mmol) was converted, using2,2,3,3,3-pentafluoropropylamine instead of 2,2,2-trifluoroethylamine,to the title compound (100 mg, 75%) which was obtained as a white solid.MS: m/e=460.1 [M+H]⁺.

Example 866-[3-(2-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 84f,6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.58 mmol) was converted, using isopropylamineinstead of 2,2,2-trifluoroethylamine, to the title compound (180 mg,83%) which was obtained as a colourless oil. MS: m/e=370.1 [M+H]⁺.

Example 876-[3-(2-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 84f,6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (100 mg, 0.29 mmol) was converted, using4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to thetitle compound (110 mg, 92%) which was obtained as a colourless oil. MS:m/e=412.2 [M+H]⁺.

Example 886-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester a) (E)- and/or (Z)-3-Fluoro-benzaldehyde oxime

To a suspension of 3-fluorobenzaldehyde (6.75 g, 54 mmol) andhydroxylamine hydrochloride (4.16 g, 60 mmol) in ethanol (4.3 mL) andwater (13 mL) was added ice (25 g). Then a solution of sodium hydroxide(5.5 g, 138 mmol) in water (6.5 mL) was added dropwise within a 10 minperiod (temperature rises from −8° C. to +7° C.) whereupon most of thesolid dissolves. After 30 min stirring at room temperature a white solidprecipitated and the resulting mixture was then diluted with water andacidified with HCl (4 N). The white precipitate was then filtered off,washed with water and dried under high vacuum to afford the titlecompound (7.0 g, 93%) which was obtained as a white solid. MS m/e (EI):139.1 [M].

b) (E)- and/or (Z)—N-Hydroxy-3-fluoro-benzenecarboximidoyl chloride

To a solution of (E)- and/or (Z)-3-fluoro-benzaldehyde oxime (6.9 g, 50mmol) in DMF (50 mL) was added N-chlorosuccinimide (6.6 g, 50 mmol)portionwise over 1 h, keeping the temperature below 35° C. The reactionmixture was stirred at room temperature for 1 h. The mixture was thenpoured onto ice-water, and extracted with ethyl acetate. The combinedorganic layers were then washed with water and brine, dried over sodiumsulfate and evaporated to afford the title compound (6.3 g, 73%) whichwas obtained as an off white solid. MS m/e (EI): 173.1 [M].

c) 3-(3-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester

To a solution of (E)- and/or (Z)—N-hydroxy-3-fluoro-benzenecarboximidoylchloride (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0° C. followed by the dropwiseaddition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resultingmixture allowed to warm up to room temperature overnight. The mixturewas then poured onto ice-water, and extracted with diethylether. Thecombined organic layers were then washed with water and brine, driedover sodium sulfate and evaporated. Purification by chromatography(SiO₂, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound(6.3 g, 39%) which was obtained as a white solid. MS: m/e=250.1 [M+H]⁺.

d) [3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

To a solution of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylicacid ethyl ester (6.18 g, 25 mmol) in THF (320 mL) was added portionwiselithiumaluminiumhydride (528 mg, 14 mmol) at 0° C. and the reactionmixture was stirred at room temperature for 3 h. The mixture was thencooled to 0° C. and water (518 μL) added followed by sodium hydroxide(15% solution, 518 μL) and then again water (1.5 mL) and the mixturethen stirred overnight at room temperature. The precipitate was thenfiltered off and washed with THF. The combined washings and filtratewere then evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (3.9 g,75%) which was obtained as a yellow solid. MS: m/e=208.3 [M+H]⁺.

e) 6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester

To a suspension of sodium hydride (55% dispersion in mineral oil, 852mg, 20 mmol) in THF (27 mL) was added a solution of[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol)in THF (54 mL) at 0° C. and the reaction mixture warmed to roomtemperature over 30 min. Then a solution of methyl 6-chloronicotinate(3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and thereaction mixture was stirred at room temperature overnight. The reactionmixture was then poured into aqueous sodium chloride (saturated) and themixture was extracted with ethyl acetate. The combined organic layerswere then washed with water and brine and then dried over sodiumsulfate, filtered and evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=7:3) afforded the title compound (4.1 g, 68%)which was obtained as a white solid. MS: m/e=343.1 [M+H]⁺.

Example 896-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) wasadded dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine(119 mg, 94 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixturewas stirred at room temperature for 1 h. Then a solution of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. Theresulting mixture was then heated at 85-95° C. for 2 h and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (122 mg, 99%) whichwas obtained as a white solid. MS: m/e=410.1 [M+H]⁺.

Example 90N-Cyclopropylmethyl-6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) wasadded dropwise (exothermic) to a solution of cyclopropylmethylamine (85mg, 103 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture wasstirred at room temperature for 1 h. Then a solution of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. Theresulting mixture was then heated at 85-95° C. overnight and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (78 mg, 68%) which wasobtained as an off white solid. MS: m/e=382.3 [M+H]⁺.

Example 916-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamidea) 6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid

As described for example 41a,6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (3.3 g, 10 mmol), instead of(3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-aceticacid ethyl ester, was converted, to the title compound (3.0 g, 95%)which was obtained as an off white solid. MS: m/e=327.4 [M−H]⁻.

b)6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

To a solution of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(98.5 mg, 0.3 mmol) in DMF (1.5 mL) were added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(106 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (257 μL, 1.5 mmol) andisopropylamine (28.3 μL, 0.33 mmol). The resulting reaction mixture wasstirred overnight at room temperature. Concentration and purification bychromatography (SiO₂, heptane:ethyl acetate=100:0 to 0:100) afforded thetitle compound 57 mg, 51%) as an off white solid. MS: m/e=370.1 [M+H]⁺.

Example 92N-Cyclopropyl-6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) wasadded dropwise (exothermic) to a solution of cyclopropylamine (69 mg, 84μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirredat room temperature for 1 h. Then a solution of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. Theresulting mixture was then heated at 85-95° C. for 3 h and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (100 mg, 91%) whichwas obtained as a white solid. MS: m/e=368.0 [M+H]⁺.

Example 936-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 92,6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) was converted, using4-aminotetrahydropyran instead of cyclopropylamine, to the titlecompound (105 mg, 85%) which was obtained as a white solid. MS:m/e=412.5 [M+H]⁺.

Example 94{6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone

As described for example 90,6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) was converted, using morpholine insteadof cyclopropylmethylamine, to the title compound (60 mg, 50%) which wasobtained as a colourless gum. MS: m/e=398.3 [M+H]⁺.

Example 95{6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone

A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) wasadded dropwise (exothermic) to a solution of thiomorpholine (124 mg, 120μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirredat room temperature for 1 h. Then a solution of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. Theresulting mixture was then heated at 85-95° C. for 4 h and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:3) afforded the title compound (124 mg, 100%) whichwas obtained as a light yellow gum. MS: m/e=414.4 [M+H]⁺.

Example 96(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone

As described for example 95,6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) was converted, usingthiomorpholine-S,S-dioxide instead of thiomorpholine, to the titlecompound (133 mg, 100%) which was obtained as a white foam. MS:m/e=446.0 [M+H]⁺.

Example 976-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester a) (E)- and/or (Z)-3-Chloro-benzaldehyde oxime

To a suspension of 3-chlorobenzaldehyde (50 g, 355 mmol) andhydroxylamine hydrochloride (38 g, 543 mmol) in ethanol (200 mL)containing sodium acetate (46 g, 558 mmol) was heated under reflux for 3h. After 30 min stirring at room temperature a white solid precipitatedand the resulting mixture was then diluted with water and acidified withHCl (4 N). The white precipitate was then filtered off, washed withwater and dried under high vacuum to afford the title compound (54 g,98%) which was obtained as a white solid. Mp: 64-66° C.

b) (E)- and/or (Z)—N-Hydroxy-3-chloro-benzenecarboximidoyl chloride

To a solution of (E)- and/or (Z)-3-chloro-benzaldehyde oxime (54 g, 347mmol) in DMF (800 mL) was added HCl (conc., 17 mL) and the mixturecooled to room temperature. Then potassium monopersulfate triple salt(247 g, 400 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. The mixture was then poured onto ice-water, andextracted with ethyl acetate. The combined organic layers were thenwashed with water and brine, dried over sodium sulfate and evaporated toafford the title compound (66 g, 100%) which was obtained as a whitesolid. Mp: 58-60° C.

c) 3-(3-Chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester

To a suspension of sodium (2.67 g, 116 mmol) in methanol (100 mL) wasadded ethyl acetoacetate (12.8 g, 11.9 mL, 110 mmol) at room temperatureover 15 minutes and then a solution of (E)- and/or(Z)—N-hydroxy-3-chloro-benzenecarboximidoyl chloride (19.0 g, 100 mmol)in methanol (100 mL) was added over 20 minutes and the resulting mixtureallowed to stir for 4 h at room temperature. The mixture was then pouredonto water and cooled to 5° C., filtered and evaporated. Purification byrecrystallisation from ethanol afforded the title compound (10.1 g, 40%)which was obtained as a white solid. Mp: 71-73° C.

d) 3-(3-Chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid

To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylicacid ethyl ester (9.1 g, 36 mmol) in ethanol (50 mL) was added aqueoussodium hydroxide (4 N, 10 mL). After heating at reflux for 1 h themixture was cooled to room temperature and acidified with HCl (4 N, 10mL) and water (10 mL) at 0° C. Purification by filtration and dryingafforded the title compound (8.3 g, 97%) which was obtained as a whitesolid. Mp: 171-173° C.

e) [3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylicacid (4.8 g, 20 mmol in THF (50 mL) at −10° C. was added triethylamine(2.9 mL, 21 mmol) and then a solution of ethylchloroformate (1.96 mL, 20mmol) in THF (10 mL) added keeping the temperature below −5° C. After 1h the mixture was filtered and the filtrate cooled to −10° C. and asuspension of sodiumborohydride (2.0 g, 50 mmol) in water (10 mL) addedover 15 minutes keeping the temperature below −5° C. The mixture wasthen allowed to warm up to room temperature over 2 h and diluted withsodium hydroxide (2 N, 30 mL) and extracted with ethyl acetate. Thecombined organic layers were then washed with water and brine, driedover sodium sulfate and evaporated to afford the title compound (3.5 g,78%) which was obtained as a clear oil which solidified with time as awhite solid. Mp: 66-68° C.

f) 6-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester

As described for example 88e,[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (224 mg, 1.0mmol), instead of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol,was converted, to the title compound (185 mg, 52%) which was obtained asan off-white solid. MS: m/e=359.4 [M+H]⁺.

Example 986-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamidea) 6-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid

As described for example 91a,6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (734 mg, 2.1 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, to the title compound (592 mg, 84%) whichwas obtained as a white solid. MS: m/e=343.4 [M−H]⁻.

b)6-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

To a solution of6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69mg, 0.2 mmol) in DMF (300 μL) were added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and2,2,2-trifluoroethylamine (17.3 μL, 0.22 mmol). The resulting reactionmixture was stirred for 1 h at room temperature. Concentration andpurification by chromatography (SiO₂, heptane:ethyl acetate=100:0 to1:1) afforded the title compound (30 mg, 35%) as a white solid. MS:m/e=426.1 [M+H]⁺.

Example 996-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamide

As described for example 98b,6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69mg, 0.2 mmol) was converted, using cyclopropanemethylamine instead of2,2,2-trifluoroethylamine, to the title compound (39 mg, 49%) which wasobtained as a white solid. MS: m/e=398.0 [M+H]⁺.

Example 1006-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide

As described for example 98b,6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69mg, 0.2 mmol) was converted, using cyclopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (55 mg, 72%) which wasobtained as a white solid. MS: m/e=384.0 [M+H]⁺.

Example 1016-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 98b,6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine, to the title compound (76 mg, 89%) which wasobtained as a white solid. MS: m/e=428.5 [M+H]⁺.

Example 102{6-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone

As described for example 98b,6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69mg, 0.2 mmol) was converted, using thiomorpholine-S,S-dioxide instead of2,2,2-trifluoroethylamine, to the title compound (80 mg, 87%) which wasobtained as a white solid. MS: m/e=462.1 [M+H]⁺.

Example 1036-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester a) (E)- and/or (Z)-4-Fluoro-benzaldehyde oxime

As described for example 88a, 4-fluorobenzaldehyde (24.8 g, 200 mmol)was converted, instead of 3-fluorobenzaldehyde, to the title compound(23.3 g, 84%) which was obtained as a white solid. MS: m/e=139.1 [M]₊.

b) (E)- and/or (Z)—N-Hydroxy-4-fluoro-benzenecarboximidoyl chloride

As described for example 88b, (E)- and/or (Z)-4-fluoro-benzaldehydeoxime 4-fluorobenzaldehyde (23.3 g, 167 mmol) was converted, instead of(E)- and/or (Z)-3-fluoro-benzaldehyde oxime, to the title compound (25.9g, 89%) which was obtained as an off white solid. MS: m/e=173.0 [M]⁺.

c) 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester

As described for example 88c, (E)- and/or(Z)—N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol)was converted, instead of (E)- and/or(Z)—N-hydroxy-3-fluoro-benzenecarboximidoyl chloride, to the titlecompound (9.8 g, 44%) which was obtained as an off white solid. MS:m/e=250.1 [M+H]⁺.

d) [3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 88d,3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester(3.0 g, 12 mmol) was converted, instead of3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (1.8 g, 71%) which was obtained as a white solid. MS:m/e=208.1 [M+H]⁺.

e) 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]1-nicotinic acidmethyl ester

As described for example 88e,[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (103 mg, 0.55mmol) was converted, instead of[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (81 mg, 47%) which was obtained as a light yellow solid. MS:m/e=343.3 [M+H]⁺.

Example 1046-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid

As described for example 91a,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (1.4 g, 4.2 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, to the title compound (1.1 g, 78%) whichwas obtained as a white solid. MS: m/e=327.3 [M−H]⁻.

Example 1056-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 98b,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol), instead of6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,was converted, to the title compound (61 mg, 50%) which was obtained asa white solid. MS: m/e=410.4 [M+H]⁺.

Example 106N-Cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol) was converted, using cyclopropanemethylamine instead of2,2,2-trifluoroethylamine, to the title compound (74 mg, 65%) which wasobtained as a white solid. MS: m/e=382.4 [M+H]⁺.

Example 1076-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol) was converted, using isopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (87 mg, 79%) which wasobtained as an off white solid. MS: m/e=370.0 [M+H]⁺.

Example 108N-Cyclopropyl-6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol) was converted, using cyclopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (47 mg, 43%) which wasobtained as a white solid. MS: m/e=368.0 [M+H]⁺.

Example 1096-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol) was converted, using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine, to the title compound (105 mg, 85%) which wasobtained as a white solid. MS: m/e=412.5 [M+H]⁺.

Example 110{6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol) was converted, using morpholine instead of2,2,2-trifluoroethylamine, to the title compound (16 mg, 13%) which wasobtained as a white solid. MS: m/e=398.3 [M+H]⁺.

Example 111{6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol) was converted, using thiomorpholine instead of2,2,2-trifluoroethylamine, to the title compound (46 mg, 37%) which wasobtained as a light yellow solid. MS: m/e=414.4 [M+H]⁺.

Example 112(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99mg, 0.33 mmol) was converted, using thiomorpholine-S,S-dioxide insteadof 2,2,2-trifluoroethylamine, to the title compound (73 mg, 55%) whichwas obtained as a white solid. MS: m/e=446.1 [M+H]⁺.

Example 1133-{6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-oxetan-3-ola)5-Bromo-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine

To a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol(500 mg, 2.41 mmol) in THF (5 mL) at room temperature was added sodiumhydride (55% dispersion in mineral oil, 137 mg, 3.1 mmol) and thereaction mixture stirred at room temperature for 1 h. Then a solution of2-chloro-5-bromo-pyridine (484 mg, 2.41 mmol) in THF (5 mL) was added atroom temperature and the reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was then diluted with methanoland water and the mixture was extracted with ethyl acetate. The combinedorganic layers were then washed with water and brine and then dried oversodium sulfate, filtered and evaporated. Purification by chromatography(SiO₂, heptane:ethyl acetate=9:1 to 4:1) afforded the title compound(128 mg, 15%) which was obtained as a colourless oil. MS:m/e=363.1/365.1 [M+H]⁺.

b)3-{6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-oxetan-3-ol

A solution of5-bromo-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine(110 mg, 0.3 mmol) in THF (3 mL) was treated at −78° C. withn-butyllithium (1.6 M solution in hexanes, 189 μL, 0.3 mmol) and thenwith 3-oxetanone (23.0 mg, 0.3 mmol). After 20 minutes methanol wasadded and the mixture was warmed to room temperature. Concentration andpurification by chromatography (silicagel, heptane:ethyl acetate=85:15to 8:3) to afforded the title product (32 mg, 30%) which was obtained asa colourless oil. MS: m/e=357.1 [M+H]⁺.

Example 114{6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1R,5S)-6-oxa-3-aza-bicyclo[3.1.1]hept-3-yl-methanone

As described for example 105,6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (36mg, 0.11 mmol) was converted, usingrac-6-oxa-3-aza-bicyclo[3.1.1]heptane instead of2,2,2-trifluoroethylamine, to the title compound (10 mg, 22%) which wasobtained as a colourless gum. MS: m/e=410.4 [M+H]⁺.

Example 1156-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester a) (E)- and/or (Z)-4-Chloro-benzaldehyde oxime

As described for example 88a, 4-chlorobenzaldehyde (25.0 g, 178 mmol)was converted, instead of 3-fluorobenzaldehyde, to the title compound(27.0 g, 97%) which was obtained as an off white solid. MS: m/e=155.1[M]⁺.

b) (E)- and/or (Z)—N-Hydroxy-4-chloro-benzenecarboximidoyl chloride

As described for example 88b, (E)- and/or (Z)-4-chloro-benzaldehydeoxime 4-fluorobenzaldehyde (27.0 g, 173 mmol) was converted, instead of(E)- and/or (Z)-3-fluoro-benzaldehyde oxime, to the title compound (28.4g, 86%) which was obtained as a light yellow solid. MS: m/e=189.1 [M]⁺.

c) 3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester

As described for example 88c, (E)- and/or(Z)—N-hydroxy-4-chloro-benzenecarboximidoyl chloride (26.0 g, 137 mmol)was converted, instead of (E)- and/or(Z)—N-hydroxy-3-fluoro-benzenecarboximidoyl chloride, to the titlecompound (15.2 g, 42%) which was obtained as a light yellow solid. MS:m/e=266.1 [M+H]⁺.

d) [3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 88d,3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester(373 mg, 1.4 mmol) was converted, instead of3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (204 mg, 65%) which was obtained as a white solid.MS: m/e=224.1 [M+H]⁺.

e) 6-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester

As described for example 88e,[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (2.0 g, 9 mmol)was converted, instead of[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (2.4 g, 74%) which was obtained as a light yellow solid. MS:m/e=359.0 [M+H]⁺.

Example 1166-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid

As described for example 91a,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (880 mg, 4.2 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, to the title compound (832 mg, 98%) whichwas obtained as an off white solid. MS: m/e=343.1 [M−H]⁻.

Example 1176-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 401 μL, 0.8 mmol) wasadded dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine(79 mg, 63 μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture wasstirred at room temperature for 1 h. Then a solution of6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (72 mg, 0.2 mmol) in dioxane (2.5 mL) was added. Theresulting mixture was then heated at 85-95° C. for 1 h and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (66 mg, 77%) which wasobtained as a white solid. MS: m/e=426.0 [M+H]⁺.

Example 1186-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamide

As described for example 117,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (144 mg, 0.4 mmol) was converted, usingcyclopropanemethylamine instead of 2,2,2-trifluoroethylamine, to thetitle compound (111 mg, 70%) which was obtained as a white solid. MS:m/e=398.4 [M+H]⁺.

Example 1196-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 8b,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(103 mg, 0.3 mmol), instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, wasconverted, using isopropylamine instead of methylamine, to the titlecompound (88 mg, 76%) which was obtained as an off white solid. MS:m/e=368.0 [M+H]⁺.

Example 1206-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide

As described for example 117,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (108 mg, 0.3 mmol) was converted, using cyclopropylamineinstead of 2,2,2-trifluoroethylamine, to the title compound (93 mg, 81%)which was obtained as a white solid. MS: m/e=384.1 [M+H]⁺.

Example 1216-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 117,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (108 mg, 0.3 mmol) was converted, using4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to thetitle compound (99 mg, 77%) which was obtained as a white solid. MS:m/e=428.1 [M+H]⁺.

Example 122{6-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1,6-thiomorpholin-4-yl)-methanone

As described for example 117,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (108 mg, 0.3 mmol) was converted, usingthiomorpholine-S,S-dioxide instead of 2,2,2-trifluoroethylamine, to thetitle compound (137 mg, 99%) which was obtained as a white solid. MS:m/e=462.1 [M+H]⁺.

Example 123{6-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone

As described for example 89,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (144 mg, 0.4 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, using morpholine instead of2,2,2-trifluoroethylamine, to the title compound (142 mg, 85%) which wasobtained as a white solid. MS: m/e=414.1 [M+H]⁺.

Example 124{6-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone

As described for example 117,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (72 mg, 0.2 mmol) was converted, using thiomorpholineinstead of 2,2,2-trifluoroethylamine, to the title compound (82 mg, 95%)which was obtained as a white solid. MS: m/e=430.5 [M+H]′.

Example 1256-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamidea) (E)- and/or (Z)-3,4-Difluoro-benzaldehyde oxime

As described for example 88a, 3,4-difluorobenzaldehyde (50.0 g, 338mmol), instead of 2-fluorobenzaldehyde, was converted to the titlecompound (53.1 g, 85%) which was obtained as a light yellow solid. MS:m/e=156.0 [M−H]⁻.

b) (E)- and/or (Z)-3,4-Difluoro-N-hydroxy-benzenecarboximidoyl chloride

As described for example 88b, (E)- and/or (Z)-3,4-difluoro-benzaldehydeoxime (44.8 g, 285 mmol), instead of (E)- and/or(Z)-2-fluoro-benzaldehyde oxime, was converted to the title compound(54.6 g, 100%) which was obtained as a yellow solid. MS: m/e=191.1 [M]⁺.

c) 3-(3,4-Difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethylester

As described for example 88c, (E)- and/or(Z)-3,4-difluoro-N-hydroxy-benzenecarboximidoyl chloride (54.6 g, 285mmol), instead of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride, was converted tothe title compound (29.5 g, 39%) which was obtained as an off whitesolid. MS: m/e=268.2 [M+H]⁺.

d) [3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 88d,3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester(28.5 g, 107 mmol), instead of3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester,was converted to the title compound (24.0 g, 48%) which was obtained asa light yellow solid. MS: m/e=226.2 [M+H]′.

e) 6-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]1-nicotinicacid methyl ester

As described for example 88e,[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.0 g, 22.2mmol), instead of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol,was converted to the title compound (5.2 g, 65%) which was obtained as awhite solid. MS: m/e=361.2 [M+H]⁺.

f)6-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 1.1 mL, 2.2 mmol) wasadded dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine(250 mg, 2.2 mmol) in dioxane (10 mL) and the resulting mixture wasstirred at room temperature for 1 h. Then a solution of6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) in dioxane (10 mL) was added. Theresulting mixture was then heated at 85-95° C. for 16 h and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=95:5 to 1:1) afforded the title compound (150 mg, 63%) which wasobtained as a white solid. MS: m/e=482.2 [M+H]′.

Example 1266-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 125,6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using isopropylamineinstead of 2,2,2-trifluoroethylamine, to the title compound (160 mg,74%), which was obtained as a white solid. MS: m/e=386.5 [M−H]−.

Example 1276-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 125,6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to thetitle compound (120 mg, 50%) which was obtained as a white solid. MS:m/e=430.3 [M+H]⁺.

Example 1286-(3-Phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester a) rac-3-Phenyl-5-hydroxy-5-(trifluoromethyl)isoxazoline

Prepared according to J. Org. Chem., 1995, 60, 3907. A solution ofbenzoyltrifluoroacetone (21 g, 97 mmol) was added dropwise over 1 h, at20-30° C., to a solution of hydroxylamine HCl (6.82 g, 98 mmol)containing sodium hydroxide (2 N, 51 mL, 102 mmol) and the resultingmixture heated under reflux for 45 min. After cooling to roomtemperature, the mixture was poured into ice-water (500 mL), theprecipitate was filtered off, washed with water and dried under vacuumto afford the title compound (20.51 g, 91%) which was obtained as awhite solid. MS: m/e=230.2 [M−H]⁻.

b) 3-Phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole

Prepared according to J. Org. Chem., 1995, 60, 3907. A solution ofrac-3-phenyl-5-hydroxy-5-(trifluoromethyl)isoxazoline (20.4 g, 88 mmol)in trifluoroacetic acid (602 g, 404 mL, 5.3 mol) was heated under refluxfor 24 h. After cooling to room temperature, the mixture was addedcarefully to a sodium carbonate solution (3 N, 880 mL) under ice-bathcooling until the reaction mixture was pH 7. The mixture was thenextracted with tert-butylmethylether and the combined organic layersdried over sodium sulfate, filtered and evaporated. The residue was thenevaporated and triturated with water to afford the title compound (17.3g, 92%) which was obtained as a white solid. MS: m/e=214.1 [M+H]⁺.

c) 3-Phenyl-5-trifluoromethyl-isoxazole-4-carboxylic acid

To a solution of 2,2,6,6-tetramethylpiperidine (7.7 g, 9.24 mL, 54 mmol)in dry THF (62 mL) was added BuLi (1.6 M in hexane, 30.7 mL, 49 mmol) at0° C. and the resulting mixture stirred at 0° C. for 30 min. Then asolution of3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (8.72g, 41 mmol) in dry THF (41 mL) was added dropwise at 0° C. and theresulting mixture stirred at 0° C. for 1 h. The mixture was thenquenched with carbon dioxide gas and the resulting mixture stirred at 0°C. for 1 h. The mixture was then poured into HCl (1 N) and the mixturewas extracted with ethyl acetate and the combined organic layers driedover sodium sulfate, filtered and evaporated to afford the titlecompound (10.32 g, 98%) which was obtained as a light brown solid. MS:m/e=256.1 [M−H]⁻.

d) (3-Phenyl-5-trifluoromethyl-isoxazol-4-yl)-methanol

To a solution of 3-phenyl-5-trifluoromethyl-isoxazole-4-carboxylic acid(5.0 g, 19 mmol in THF (60 mL) at −10° C. was added triethylamine (2.0g, 2.71 mL, 19 mmol) and then a solution of ethylchloroformate (2.1 g,1.9 mL, 19 mmol) in THF (10 mL) added keeping the temperature below −5°C. After 30 min the mixture was filtered and the filtrate cooled to −10°C. and a suspension of sodiumborohydride (1.8 g, 49 mmol) in water (20mL) added over 15 minutes keeping the temperature below −5° C. Themixture was then allowed to warm up to room temperature overnight anddiluted with HCl (1 N) and extracted with ethyl acetate. The combinedorganic layers were then washed with water and brine, dried over sodiumsulfate and evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (3.1 g,66%) as a white solid. MS: m/e=243.1 [M]′.

e) 6-(3-Phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester

To a solution of (3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-methanol(100 mg, 0.41 mmol) in THF (5 mL) was added 6-hydroxy-nicotinic acidmethyl ester (69.3 mg, 0.45 mmol) and triphenylphosphine (162 mg, 0.62mmol) at ambient temperature under an argon atmosphere. Then diethylazodicarboxylate (96 μL, 0.62 mmol) was added and the reaction mixturewas heated at 50° C. for 2 h. After cooling to room temperature themixture was evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (66 mg,42%) as an off-whit solid. MS: m/e=379.5 [M+H]⁺.

Example 129N-Methyl-6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 90,6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (100 mg, 0.26 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester was converted, using methylamine (2 M in THF) instead ofcyclopropylmethylamine, to the title compound (71 mg, 72%) which wasobtained as a white solid. MS: m/e=378.4 [M+H]⁺.

Example 130N-Ethyl-6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 117,6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (100 mg, 0.26 mmol),6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (144 mg, 0.4 mmol) was converted, using ethylamine (2 M inTHF) instead of 2,2,2-trifluoroethylamine, to the title compound (80 mg,77 which was obtained as a white solid. MS: m/e=392.3 [M+H]⁺.

Example 131N-(2-Hydroxy-ethyl)-6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 129,6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (100 mg, 0.26 mmol) was converted, using ethanolamineinstead of methylamine (2 M in THF), to the title compound (26 mg, 24%)which was obtained as an off white solid. MS: m/e=408.3 [M+H]⁺.

Example 132N-Cyclopropylmethyl-6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 529 μL, 1.1 mmol) wasadded dropwise (exothermic) to a solution of cyclopropanemethylamine (75mg, 91 μL, 1.1 mmol) in dioxane (7 mL) and the resulting mixture wasstirred at room temperature for 1 h. Then a solution of6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (100 mg, 0.26 mmol) in dioxane (4 mL) was added. Theresulting mixture was then heated at 85-95° C. for 6 h and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (92 mg, 83%) which wasobtained as an off white solid. MS: m/e=418.3 [M+H]⁺.

Example 133N-Isopropyl-6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 529 μL, 1.1 mmol) wasadded dropwise (exothermic) to a solution of isopropylamine (63 mg, 91μL, 1.1 mmol) in dioxane (7 mL) and the resulting mixture was stirred atroom temperature for 1 h. Then a solution of6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (100 mg, 0.26 mmol) in dioxane (4 mL) was added. Theresulting mixture was then heated at 85-95° C. for 5 h and then cooledto room temperature and then poured into water and extracted with ethylacetate which was then washed with brine, dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (102 mg, 95%) whichwas obtained as a white solid. MS: m/e=406.4 [M+H]⁺.

Example 134N-Cyclopropyl-6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 89,6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (100 mg, 0.26 mmol), instead of6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, using cylopropylamine instead ofmorpholine, to the title compound (100 mg, 94%) which was obtained as awhite solid. MS: m/e=404.5 [M+H]⁺.

Example 1356-(3-Phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 90,6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (100 mg, 0.26 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester was converted, using 4-aminotetrahydropyran instead ofcyclopropylmethylamine, to the title compound (111 mg, 94%) which wasobtained as a white solid. MS: m/e=448.3 [M+H]⁺.

Example 1366-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester a)4,4,4-Trifluoro-1-(4-fluoro-phenyl)-butane-1,3-dione

To a solution of ethyl trifluoroacetate (23.9 mL, 199 mmol) intertbutylmethylether (230 mL) containing sodium methoxide (5.4 M, 39.6mL, 214 mmol) was added 4-fluoroacetophenone (25 g, 181 mmol) and theresulting mixture stirred at room temperature for 3 h and then pouredinto ice-water. The mixture was then diluted with HCl (2 N, 200 mL) andthen extracted with ethyl acetate. The combined organic extracts werethen dried over sodium sulfate and evaporated to afford the titlecompound (40.9 g, 97%) which was obtained as an orange oil. MS:m/e=232.9 [M−H]⁻.

b) rac-3-(4-Fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-ol

As described for example 128a,4,4,4-trifluoro-1-(4-fluoro-phenyl)-butane-1,3-dione (12.39 g, 174.7mmol), instead of benzoyltrifluoroacetone, was converted to the titlecompound (39.6 g, 92%) which was obtained as a light brown solid. MS:m/e=247.9 [M−H]⁻.

c) 3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazole

As described for example 128b,rac-3-(4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-ol(35.6 g, 142.9 mmol), instead of3-phenyl-5-hydroxy-5-(trifluoromethyl)isoxazoline, was converted to thetitle compound (32.2 g, 98%) which was obtained as a light brown solid.MS: m/e=298.1 [M+H]⁺.

d) 3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazole-4-carboxylic acid

As described for example 128c,3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazole (40 g, 173 mmol),instead of3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole, wasconverted to the title compound (23.1 g, 49%) which was obtained as ayellow solid. MS: m/e=294.0 [M−H]⁻.

e) [3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-methanol

As described for example 128d,3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazole-4-carboxylic acid (3.0g, 11 mmol), instead of3-phenyl-5-trifluoromethyl-isoxazole-4-carboxylic acid, was converted tothe title compound (1.58 g, 56%) which was obtained as a yellow solid.MS: m/e=262.0 [M+H]⁺.

f)6-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]1-nicotinicacid methyl ester

As described for Example 128e,[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-methanol (100 mg,0.38 mmol), instead of(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-methanol, was converted tothe title compound (54 mg, 36%) which was obtained as a white solid. MS:m/e=397.0 [M+H]⁺.

Example 1376-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-N-methyl-nicotinamide

As described for example 129,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol), instead of6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester, was converted to the title compound (66 mg, 66%) which wasobtained as an off white solid. MS: m/e=396.1 [M+H]⁺.

Example 138N-Ethyl-6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 137,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol) was converted, using ethylamineinstead of methylamine, to the title compound (75 mg, 72%) which wasobtained as a white solid. MS: m/e=410.4 [M+H]⁺.

Example 1396-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamide

As described for example 137,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol) was converted, using ethanolamineinstead of methylamine to the title compound (19 mg, 18%) which wasobtained as a white solid. MS: m/e=426.1 [M+H]⁺.

Example 1406-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 92,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, using 2,2,2-trifluoroethylamine instead ofcyclopropylamine, to the title compound (115 mg, 98%) which was obtainedas a white solid. MS: m/e=464.3 [M+H]⁺.

Example 141N-Cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 137,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol) was converted, usingcyclopropanemethylamine instead of methylamine, to the title compound(96 mg, 87%) which was obtained as an off white solid. MS: m/e=436.0[M+H]⁺.

Example 1426-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 137,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol) was converted, usingisopropylamine instead of methylamine, to the title compound (104 mg,97%) which was obtained as an off white solid. MS: m/e=424.1 [M+H]⁺.

Example 143N-Cyclopropyl-6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 89,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, using cylopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (90 mg, 54%) which wasobtained as a white solid. MS: m/e=422.1 [M+H]⁺.

Example 1446-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 137,6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol) was converted, using4-aminotetrahydropyran instead of methylamine (2 M in THF), to the titlecompound (94 mg, 80%) which was obtained as a white solid. MS: m/e=466.0[M+H]⁺.

Example 145(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone

A solution of trimethylaluminium (2 M in toluene, 504 μL, 1.0 mmol) wasadded dropwise (exothermic) to a solution of thiomorpholine-S,S-dioxide(136 mg, 1.0 mmol) in dioxane (7 mL) and the resulting mixture wasstirred at room temperature for 1 h. Then a solution of6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.25 mmol) in dioxane (4 mL) was added. Theresulting mixture was then heated at 85-95° C. for 4 days and thencooled to room temperature and then poured into water and extracted withethyl acetate which was then washed with brine, dried over sodiumsulfate and evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (32 mg,25%) which was obtained as an off white solid. MS: m/e=500.0 [M+H]⁺.

Example 1466-(5-Methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamidea) 5-Methyl-3-pyridin-4-yl-isoxazole-4-carboxylic acid ethyl ester

To a suspension of N-chlorosuccinimide (10.9 g, 81.9 mmol) in chloroform(50 mL) was added pyridine (0.66 mL, 8.2 mmol) and a solution ofpyridine-4-carboxaldoxime (10.0 g, 81.2 mmol) in chloroform (150 mL)during 15 min at ambient temperature. After stirring for 30 min at thistemperature a solution of ethyl (E)-3-(1-pyrrolidino)-2-butenoate (15.0g, 81.9 mmol) in chloroform (10 mL) was added. The resulting suspensionwas warmed to 50° C. and a solution of triethylamine (12 mL, 86 mmol) inchloroform (10 mL) was added dropwise over a period of 1 h. Stirring wascontinued for 0.5 h at 50° C. and for 30 h at ambient temperature. Thedark brown solution was washed with water (100 mL) and the aqueouslayers were extracted with dichloromethane (50 mL) and dried over sodiumsulfate. Concentration was followed by trituration of the residue in amixture of tert-butylmethylether and heptane (1:1, 20 mL) affording thetitle compound (8.09 g, 24%) as a brown solid. MS: m/e=233.1 [M+H]⁺.

b) (5-Methyl-3-pyridin-4-yl-isoxazol-4-yl)-methanol

To a solution of 5-methyl-3-pyridin-4-yl-isoxazole-4-carboxylic acidethyl ester (7.06 g, 17.3 mmol) in THF (350 mL) was added at 5° C.lithiumaluminumhydride (635 mg, 16.7 mmol). After stirring for 2 h atthis temperature further lithiumaluminumhydride (318 mg, 8.4 mmol) wasadded and stirred for 1 h at 5° C. Water (1.9 mL) was added carefullyfollowed by aqueous sodium hydroxide (15%, 1.9 mL) and water (0.540 mL).The resulting suspension was stirred for 15 min at ambient temperatureand filtered over Hyflo®. Concentration and purification bychromatography (SiO₂, heptane:ethyl acetate=50:50 to 0:100) afforded thetitle compound (2.15 g, 65%) as a light yellow solid. MS: m/e=191.2[M+H]⁺.

c) 6-(5-Methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid

A solution of (5-methyl-3-pyridin-4-yl-isoxazol-4-yl)-methanol (1.00 g,5.26 mmol) in THF (15 mL) was cooled to 0° C. and sodium hydride (55%dispersion in mineral oil, 252 mg, 5.78 mmol) was added carefully underan atmosphere of nitrogen. After the resulting suspension was stirredfor 0.5 h at ambient temperature methyl 6-chloronicotinate (1.08 g, 6.31mmol) was added and the suspension was stirred for 18 h at thistemperature.

The reaction mixture was treated with a aqueous sodium hydroxide (1 N,15.8 mL, 15.8 mmol) and stirred for 0.5 h at 70° C. The solution wascooled to ambient temperature, diluted with water (15 mL) and washedwith tert-butylmethylether (15 mL). The organic layers were extractedwith water (20 mL) and the combined aqueous layers were acified to pH=4with a aqueous hydrochloric acid (25%). After the resulting suspensionwas stirred for 0.5 h at ambient temperature it was filtered off andwashed with water (20 mL) affording the title compound (1.60 g, 97%)which was obtained as a white solid MS: m/e=310.2 [M+H]⁺.

d)6-(5-Methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 92,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg,0.3 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (103 mg, 0.3 mmol) was converted, using2,2,2-trifluoroethylamine instead of cyclopropylamine, to the titlecompound (16 mg, 14%) which was obtained as a light brown solid. MS:m/e=393.3 [M+H]⁺.

Example 147N-Cyclopropylmethyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 90,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg,0.3 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted to the title compound (69 mg, 63%) which wasobtained as an off white solid. MS: m/e=365.1 [M+H]′.

Example 148N-Cyclopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 146d,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg,0.64 mol) was converted, using cyclopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (trituration withtert-butylmethylether, 194 mg, 86%) which was obtained as a white solid.MS: m/e=351.3 [M+H]⁺.

Example 149N-Isopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 12,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg,0.64 mol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was convertedusing isopropylamine instead of 2,2,2-trifluoroethylamine to the titlecompound (trituration with tert-butylmethylether, 158 mg, 70%) which wasobtained as a white solid. MS: m/e=353.3 [M+H]⁺.

Example 1506-(5-Methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 12,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg,0.64 mol) instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was convertedusing 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine to thetitle compound (trituration with tert-butylmethylether, 178 mg, 70%)which was obtained as a white solid. MS: m/e=395.2 [M+H]⁺.

Example 151[6-(5-Methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone

As described for example 147,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg,0.3 mmol) was converted, using morpholine instead ofcyclopropylmethylamine, to the title compound (58 mg, 51%) which wasobtained as an off white solid. MS: m/e=381.0 [M+H]⁺.

Example 152[6-(5-Methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone

As described for example 147,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg,0.3 mmol) was converted, using thiomorpholine instead ofcyclopropylmethylamine, to the title compound (56 mg, 47%) which wasobtained as an off white solid. MS: m/e=397.3 [M+H]⁺.

Example 153(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-[6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 147,6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg,0.3 mmol) was converted, using thiomorpholine-S,S-dioxide instead ofcyclopropylmethylamine, to the title compound (75 mg, 58%) which wasobtained as an off white solid. MS: m/e=429.4 [M+H]⁺.

Example 154 6-(5-Methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinicacid methyl ester a) (E)- and/or (Z)—N-Hydroxy-3-pyridinecarboximidoylchloride

As described for example 88b, 3-pyridinealdoxime (25.0 g, 205 mmol),instead of (E)- and/or (Z)-3-fluoro-benzaldehyde oxime, was converted,to the title compound (18.8 g, 59%) which was obtained as a light brownsolid. MS: m/e=157.0 [M+H]′.

b) 5-Methyl-3-pyridin-3-yl-isoxazole-4-carboxylic acid ethyl ester

As described for example 88c, (E)- and/or(Z)—N-hydroxy-3-pyridinecarboximidoyl chloride (18.6 g, 119 mmol),instead of (E)- and/or (Z)—N-hydroxy-3-fluoro-benzenecarboximidoylchloride, was converted, to the title compound (8.1 g, 29%) which wasobtained as an off white solid. MS: m/e=233.1 [M+H]⁺.

c) (5-Methyl-3-pyridin-3-yl-isoxazol-4-yl)-methanol

As described for example 88d,5-methyl-3-pyridin-3-yl-isoxazole-4-carboxylic acid ethyl ester (7.9 g,34 mmol), instead of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylicacid ethyl ester, was converted, to the title compound (4.3 g, 67%)which was obtained as a light yellow liquid. MS: m/e=191.3 [M+H]⁺.

d) 6-(5-Methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester

As described for example 88e,5-methyl-3-pyridin-3-yl-isoxazole-4-carboxylic acid ethyl ester (190 mg,1.0 mmol), instead of[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, was converted, tothe title compound (174 mg, 53%) which was obtained as a white solid.MS: m/e=326.0 [M+H]⁺.

Example 1556-(5-Methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 92,6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (130 mg, 0.4 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted, using 2,2,2-trifluoroethylamine instead ofcyclopropylamine, to the title compound (139 mg, 89%) which was obtainedas an off white solid. MS: m/e=393.1 [M+H]⁺.

Example 156N-Cyclopropylmethyl-6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 90,6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (130 mg, 0.4 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, was converted to the title compound (98 mg, 67%) which wasobtained as a light yellow solid. MS: m/e=365.1 [M+H]⁺.

Example 157N-Cyclopropyl-6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 89,6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (130 mg, 0.4 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using cyclopropylamine instead of2,2,2-trifluoroethylamine, was converted to the title compound (117 mg,83%) which was obtained as an off white solid. MS: m/e=351.4 [M+H]⁺.

Example 158N-Isopropyl-6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 155,6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (130 mg, 0.4 mmol), was converted, using isopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (112 mg, 83%) which wasobtained as an off white solid. MS: m/e=353.0 [M+H]⁺.

Example 1596-(5-Methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 89,6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (130 mg, 0.4 mmol), instead of6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine, was converted to the title compound (117 mg,83%) which was obtained as an off white solid. MS: m/e=395.1 [M+H]⁺.

Example 160 (5-Methyl-3-phenyl-isoxazol-4-ylmethyl)-pyridin-2-yl-aminea) 4-Chloromethyl-5-methyl-3-phenyl-isoxazole

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (4.5 g, 236mmol) in dichloromethane (50 mL) was added at 0° C. thionyl chloride(3.6 g, 2.7 mL, 306 mmol) dropwise over 3 min and the solution stirredat 0° C. for 2 h. After this time, the mixture was diluted with water(50 mL) and the organic phase separated and washed with brine. Theaqueous phase was extracted with dichloromethane and the combinedextracts dried over sodium sulfate, filtered and evaporated to affordthe title compound (4.6 g, 93%) which was obtained as a light brownliquid. MS: m/e=208.1 [M+H]⁺.

b) (5-Methyl-3-phenyl-isoxazol-4-ylmethyl)-pyridin-2-yl-amine

To a solution of 2-aminopyridine (109 mg, 1.2 mmol) in THF (2 mL) wasadded potassium bis(trimethylsilyl)amide (0.9 M in THF, 1.2 mL, 1.1mmol) at 0° C. under argon. After 10 min, a solution of4-chloromethyl-5-methyl-3-phenyl-isoxazole (200 mg, 1.0 mmol) in THF (1mL) was added and the resulting mixture stirred at 0° C. for 1 h. Themixture was then diluted with ethyl acetate (10 mL) and washed withwater (10 mL) and brine (10 mL). The aqueous phase was extracted withethyl acetate and the combined extracts dried over sodium sulfate,filtered and evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=4:1: to 1:1) afforded the title compound (45 mg,18%) as an off white solid. MS: m/e=266.2 [M+H]⁺.

Example 161 6-[(5-Methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinicacid methyl ester

A mixture of (5-methyl-3-phenyl-4-isoxazolyl)-methylamine (200 mg, 1.06mmol), methyl 6-chloronicotinate (182 mg, 1.06 mmol), N,N-diisopropylethyl amine (364 μL, 2.13 mmol) and DMSO (2 mL) was heated in themicrowave to 160° C. for 0.5 h. It was diluted with ethyl acetate (8 mL)and washed with aqueous sodium carbonate (saturated, 8 mL), water (8 mL)and brine (8 mL). The combined aqueous layers were extracted with ethylacetate (10 mL) and the combined organic layers were dried over sodiumsulfate. Concentration and purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (158mg, 46%) as a light yellow oil. MS: m/e=324.3 [M+H]⁺.

Example 162N-(2-Hydroxy-ethyl)-6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinamidea) 6-[(5-Methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid

To a suspension of6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid methylester (1.86 g, 5.50 mmol) in ethanol (100 mL) was added aqueous sodiumhydroxide (1 N, 17 mL, 17 mmol) and the resulting suspension was heatedto 80° C. for 0.5 h. After the solution was cooled to ambienttemperature the solvent was distilled off and the residue was dilutedwith water (50 mL) and washed with tert-butylmethylether (50 mL). Theorganic layers were extracted with aqueous sodium hydroxide (1 N, 20 mL)and the combined aqueous layers were acified with aqueous hydrochloricacid (25%) to pH=3 and were extracted with a mixture of ethyl acetateand methanol (4:1, 30 mL). Drying over sodium sulfate and concentrationafforded the title compound (1.55 g, 91%) which was obtained as a whitesolid. MS: m/e=310.3 [M+H]⁺.

b)N-(2-Hydroxy-ethyl)-6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinamide

To a mixture of6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200mg, 0.65 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (228 mg, 0.71 mmol) was added DMF (2 mL). Afterstirring for 2 min at ambient temperature N,N-diisopropyl ethyl amine(553 μL, 3.23 mmol) and ethanolamine (47 μl, 0.78 mmol) were added andthe resulting solution was stirred for 2 h at this temperature. It wasdiluted with ethyl acetate (15 mL) and washed with water (20 mL) andbrine (15 mL). The aqueous layers were extracted with ethyl acetate andthe combined organic layers were dried over sodium sulfate.Concentration and purification by chromatography (SiO₂, heptane:ethylacetate:methanol=30:70:0 to 0:95:5) afforded the title compound (200 mg,88%) as a white solid. MS: m/e=353.2 [M+H]⁺.

Example 1636-[(5-Methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-N-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-nicotinamide

As described for example 162b,6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200mg, 0.65 mmol) was converted using 1-(2-amino-ethyl)-pyrrolidin-2-oneinstead of ethanolamine to the title compound (trituration withtert-butylmethylether, 224 mg, 83%) which was obtained as a white solid.MS: m/e=420.2 [M+H]⁺.

Example 164N-Isopropyl-6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinamide

As described for example 162b,6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200mg, 0.65 mmol) was converted using isopropylamine instead ofethanolamine to the title compound (SiO₂, heptane:ethyl acetate=50:50 to0:100, 185 mg, 82%) which was obtained as a white solid. MS: m/e=351.3[M+H]⁺.

Example 165N-Cyclopropyl-6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinamide

As described for example 162b,6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200mg, 0.65 mmol) was converted using cyclopropylamine instead ofethanolamine to the title compound (SiO₂, heptane:ethyl acetate=70:30 to0:100, 201 mg, 89%) which was obtained as a white solid. MS: m/e=349.3[M+H]⁺.

Example 1666-[(5-Methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 162b,6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200mg, 0.65 mmol) was converted using 4-amino-tetrahydropyran instead ofethanolamine to the title compound (trituration withtert-butylmethylether, 168 mg, 66%) which was obtained as a white solid.MS: m/e=393.3 [M+H]⁺.

Example 1676-{[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester a)2-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione

To a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol(5.8 g, 28 mmol) in THF (339 mL) was added phthalimide (5.5 g, 37 mmol)and triphenylphosphine (9.8 g, 37 mmol) at ambient temperature under anargon atmosphere. Then a solution of diethyl azodicarboxylate (40% intoluene, 14.6 mL, 37 mmol) was added and the reaction mixture wasstirred for 1 h at room temperature. Concentration and repeatedtrituration with ethyl acetate afforded the title compound (6.3 g, 66%)as a white solid. MS: m/e=337.1 [M+H]⁺.

b) C-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine

To a solution of2-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione(6.3 g, 19 mmol) in THF (252 mL) and ethanol (22 mL) at 0° C. was addedhydrazine hydrate (7.0 g, 6.8 mL, 140 mmol) and the resulting mixturestirred at room temperature overnight. The mixture was then filtered andthe filtrate diluted with HCl (1 N) and extracted with ethyl acetate.The combined organic extracts were then washed with HCl (1 N) and theaqueous layer made basic with NaOH (6 N). The aqueous layers wereextracted with ethyl acetate and the combined organic layers washed withbrine and dried over sodium sulfate. Concentration and purification bychromatography (NH₂—SiO₂, dichloromethane) afforded the title compound(3.0 g, 77%) as a yellow oil. MS: m/e=207.3 [M+H]⁺.

c)6-{[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester

A mixture of C-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine(530 mg, 2.6 mmol), methyl 6-chloronicotinate (440 mg, 2.6 mmol),N,N-diisopropyl ethyl amine (880 μL, 5.1 mmol) and DMSO (5.1 mL) washeated in the microwave to 160° C. for 2×0.5 h and 1 h. The mixture wasthen diluted with ice-water and extracted with ethyl acetate. Thecombined organic extracts were then washed with brine and dried oversodium sulfate. Concentration and purification by chromatography (SiO₂,heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (335 mg,38%) as a yellow gum. MS: m/e=342.1 [M+H]⁺.

Example 1686-{[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(2,2,2-trifluoro-ethyl)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 500 μL, 1.0 mmol) wasadded dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine(99 mg, 79 μL, 1.0 mmol) in dioxane (4 mL) and the resulting mixture wasstirred at room temperature for 1 h. Then a solution of6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (85 mg, 0.25 mmol) in dioxane (3 mL) was added. Theresulting mixture was then heated at 85-95° C. for 2 h and then cooledto room temperature and then poured into a sodium potassium tartratesolution and extracted with ethyl acetate which was then washed withbrine, dried over sodium sulfate and evaporated. Purification bychromatography (SiO₂, heptane:ethyl acetate=100:0 to 0:100) afforded thetitle compound (88 mg, 86%) which was obtained as a white solid. MS:m/e=409.1 [M+H]⁺.

Example 1696-{[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-isopropyl-nicotinamide

As described for example 168,6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (85 mg, 0.25 mmol) was converted using isopropylamineinstead of 2,2,2-trifluoroethylamine to the title compound (30 mg, 33%)which was obtained as an off white foam. MS: m/e=369.1 [M+H]⁺.

Example 170N-Cyclopropyl-6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinamide

As described for example 168,6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (90 mg, 0.26 mmol) was converted usingcyclopropylamine instead of 2,2,2-trifluoroethylamine to the titlecompound (81 mg, 84%) which was obtained as an off white solid. MS:m/e=367.4 [M+H]⁺.

Example 1716-{[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 169,6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (90 mg, 0.26 mmol) was converted using4-amiontetrahydropyran instead of 2,2,2-trifluoroethylamine to the titlecompound (80 mg, 74%) which was obtained as a white solid. MS: m/e=411.4[M+H]⁺.

Example 1726-{[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester a)2-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione

To a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol(5.0 g, 24 mmol) in THF (290 mL) was added phthalimide (4.7 g, 32 mmol)and triphenylphosphine (8.4 g, 32 mmol) at ambient temperature under anargon atmosphere. Then a solution of diethyl azodicarboxylate (40% intoluene, 12.5 mL, 32 mmol) was added and the reaction mixture wasstirred for 1 h at room temperature. Concentration and repeatedtrituration and then purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (6.0 g, 74%) as awhite solid. MS: m/e=337.1 [M+H]⁺.

b) C-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine

As described for example 167b,2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione(5.9 mg, 18 mmol), instead of2-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione,was converted to the title compound (2.0 g, 54%) which was obtained as alight yellow oil. MS: m/e=190.3 [M+H]⁺.

c)6-{[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester

A mixture of C-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine(620 mg, 3.0 mmol), methyl 6-chloronicotinate (516 mg, 3.0 mmol),N,N-diisopropyl ethyl amine (1.0 mL, 6.0 mmol) and DMSO (6 mL) washeated in the microwave to 160° C. for 2 h. The mixture was then dilutedwith ice-water and extracted with ethyl acetate. The combined organicextracts were then washed with brine and dried over sodium sulfate.Concentration and purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1 then dichloromethane:methanol 97:3) afforded thetitle compound (335 mg, 33%) as a white foam. MS: m/e=342.1 [M+H]⁺.

Example 1736-{[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 168,6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (70 mg, 0.2 mmol), instead of6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (85 mg, 0.25 mmol) was converted to the title compound(63 mg, 75%) which was obtained as a white solid. MS: m/e=409.3 [M+H]⁺.

Example 174N-Cyclopropylmethyl-6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinamide

As described for example 173,6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (70 mg, 0.2 mmol) was converted, usingaminomethylcyclopropane instead of 2,2,2-trifluoroethylamine, to thetitle compound (80 mg, 83%) which was obtained as an off white foam. MS:m/e=381.4 [M+H]⁺.

Example 1756-{[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-isopropyl-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 410 μL, 0.8 mmol) wasadded dropwise (exothermic) to a solution of isopropylamine (48 mg, 70μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred atroom temperature for 1 h. Then a solution of6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (70 mg, 0.2 mmol) in dioxane (2.5 mL) was added. Theresulting mixture was then heated at 85-95° C. for 5 h and then cooledto room temperature and then poured into a sodium potassium tartratesolution and extracted with ethyl acetate which was then washed withbrine, dried over sodium sulfate and evaporated. Purification bychromatography (SiO₂, heptane:ethyl acetate=100:0 to 0:100) afforded thetitle compound (53 mg, 70%) which was obtained as an off white foam. MS:m/e=369.4 [M+H]⁺.

Example 176N-Cyclopropyl-6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 410 μL, 0.8 mmol) wasadded dropwise (exothermic) to a solution of cyclopropylamine (47 mg, 58μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred atroom temperature for 1 h. Then a solution of6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (70 mg, 0.2 mmol) in dioxane (2.5 mL) was added. Theresulting mixture was then heated at 85-95° C. for 5 h and then cooledto room temperature and then poured into a sodium potassium tartratesolution and extracted with ethyl acetate which was then washed withbrine, dried over sodium sulfate and evaporated. Purification bychromatography (SiO₂, heptane:ethyl acetate=100:0 to 0:100) afforded thetitle compound (45 mg, 60%) which was obtained as an off white foam. MS:m/e=367.0 [M+H]⁺.

Example 1776-{[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 176,6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (70 mg, 0.2 mmol) was converted, using4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to thetitle compound (69 mg, 82%) which was obtained as a white foam. MS:m/e=411.4 [M+H]⁺.

Example 178(1,1-Dioxo-1,6-thiomorpholin-4-yl)-(6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridin-3-yl)-methanone

As described for example 176,6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester (86 mg, 0.25 mmol) was converted, usingthiomorpholine-S,S-dioxide instead of 2,2,2-trifluoroethylamine, to thetitle compound (76 mg, 68%) which was obtained as a white foam. MS:m/e=445.4 [M+H]⁺.

Example 179 Not Encompassed by the Present InventionN-[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-acetamide a)6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine

To a suspension of2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-nitro-pyridine (2.6 g, 83.5mmol) in methanol (45 mL) was added ammonium chloride (2.23 g, 417.6mmol) and Zinc (dust, 10.92 g, 167 mmol) and the resulting mixtureheated at 70° C. for 1 h. After cooling to room temperature the mixturewas filtered and the filtrate evaporated. Purification by chromatography(SiO₂, heptane:ethyl acetate=100:0 to 4:1) afforded the title compound(2.0 g, 85%) which was obtained as a light yellow oil. MS: m/e=282.0[M+H]⁺.

b) N-[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-acetamide

To a solution of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg,0.53 mmol) in THF (4 mL) was added triethylamine (65 mg, 90 μL, 0.64mmol) and the resulting mixture cooled to 0° C. with ice. Then asolution of acetyl chloride (50 mg, 50 μL) in THF (1 mL) was added andthe resulting mixture allowed to warm up to room temperature over 1 h.The mixture was then filtered and the filtrate evaporated before beingdiluted with methanol and potassium carbonate (10 mg) added. After onehour at room temperature the mixture was extracted with dichloromethane.The combined organic layers were then washed with water and then driedover sodium sulfate, filtered and evaporated to afford the titlecompound (145 mg, 84%) which was obtained as white crystals. MS:m/e=324.0 [M+H]⁺.

Example 180 Not Encompassed by the Present InventionN-[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-oxalamicacid methyl ester

As described for example 179b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg,0.53 mmol) was converted, using methyloxalylchloride instead of acetylchloride, to the title compound (118 mg, 60%) which was obtained as awhite solid after purification by chromatography (SiO₂,dichloromethane:methanol=100:0 to 9:1). MS: m/e=368.0 [M+H]⁺.

Example 181 Not Encompassed by the Present InventionN-[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-isobutyramide

As described for example 179b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg,0.53 mmol) was converted, using isobutyrylchloride instead of acetylchloride, to the title compound (170 mg, 91%) which was obtained as awhite solid after trituration with diisopropylether. MS: m/e=352.0[M+H]⁺.

Example 182 Not Encompassed by the Present InventionCyclopropanecarboxylic acid[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-amide

As described for example 179b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg,0.53 mmol) was converted, using cyclopropanecarbonylchloride instead ofacetyl chloride, to the title compound (132 mg, 71%) which was obtainedas a white solid after trituration with diisopropylether. MS: m/e=350.0[M+H]⁺.

Example 183N-(2-Hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 2-amino-2-methyl-1-propanol instead ofmethylamine, to the title compound (130 mg, 53%) which was obtained asan off white solid. MS: m/e=380.5 [M−H]⁻.

Example 184N-(2-Methoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

A solution of trimethylaluminium (2 M in toluene, 2.0 mL, 4.0 mmol) wasadded dropwise (exothermic) to a solution of 2-methoxyethylamine (300mg, 4.0 mmol) in dioxane (3 mL) and the resulting mixture was stirred atroom temperature for 1 h. Then a solution of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0mmol) in dioxane (3 mL) was added. The resulting mixture was then heatedat 85-95° C. for 4 days and then cooled to room temperature and thenpoured into water and extracted with ethyl acetate which was then washedwith brine, dried over sodium sulfate and evaporated. Purification bychromatography (SiO₂, dichloromethane:methanol=100:0 to 9:1) affordedthe title compound (280 mg, 76%) which was obtained as a colourless oil.MS: m/e=368.1 [M+H]′.

Example 185N-(1,1-Dioxo-tetrahydro-thiophen-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 1,1-dioxo-tetrahydro-thiophen-3-ylamineinstead of methylamine, to the title compound (150 mg, 54%) which wasobtained as a white solid. MS: m/e=428.2 [M+H]⁺.

Example 1866-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(3,3,3-trifluoro-2-hydroxy-propyl)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 3-amino-1,1,1-trifluoropropan-2-ol instead ofmethylamine, to the title compound (124 mg, 46%) which was obtained as awhite solid. MS: m/e=420.1 [M−H]⁻.

Example 187(4-Hydroxy-piperidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50mmol) was converted, using 4-hydroxypiperidine instead of methylamine,to the title compound (145 mg, 73%) which was obtained as a white solid.MS: m/e=394.2 [M+H]⁺.

Example 188N-(3-Hydroxy-2,2-dimethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead ofmethylamine, to the title compound (235 mg, 59%) which was obtained as awhite solid. MS: m/e=396.2 [M+H]⁺.

Example 189N-(2-Isopropoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 2-aminoethyl isopropylether instead ofmethylamine, to the title compound (190 mg, 74%) which was obtained as awhite solid. MS: m/e=454.1 [M+OAc]⁻.

Example 190N-(2-Hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (150 mg, 0.5mmol) was converted, using rac-2-amino-1-propanol instead ofmethylamine, to the title compound (158 mg, 89%) which was obtained as awhite solid. MS: m/e=368.2 [M+H]⁺.

Example 191(3-Hydroxy-azetidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (200 mg, 0.65 mmol) and azetidin-3-ol hydrochloride (70.7 mg, 0.65mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate(100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol)and N-(3-dimethylaminopropy)-N′-ethylcarbodiimidazole hydrochloride(126.2 mg, 0.65 mmol). The resulting reaction mixture was stirredovernight at room temperature. Concentration and purification bychromatography (SiO₂, heptane:ethyl acetate=3:1 to 1:4) afforded thetitle compound (215 mg, 91%) as a colourless oil. MS: m/e=366.2 [M+H]⁺.

Example 192N-(2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using rac-(cis and trans)-2-aminocyclohexanolinstead of 2-aminoethyl isopropylether, to the title compound (130 mg,50%) which was obtained as a white solid. MS: m/e=408.4 [M+H]⁺.

Example 193N-(2-Hydroxy-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of2-aminoethyl isopropylether, to the title compound (215 mg, 49%) whichwas obtained as a white solid. MS: m/e=380.0 [M−H]⁻.

Example 194N-(1-Hydroxy-cyclopropylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 1-(aminomethyl)-cyclopropan-2-ol instead of2-aminoethyl isopropylether, to the title compound (140 mg, 57%) whichwas obtained as a white solid. MS: m/e=378.3 [M−H]⁻.

Example 195N—((R)-2-Hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

The stereoisomers ofN-(2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(example 192, 500 mg) in ethanol:heptane (1:1, 8 mL) were separatedusing a 5×50 cm Chiralpak AD column at room temperature using anisopropanol:heptane (2:8) mobile phase with UV detection at 220 nM. Theleast polar component (+ve sign of rotation) was obtained as a whitesolid (168 mg).

Example 196N—((S)-2-Hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

The stereoisomers ofN-(2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(example 192, 500 mg) in ethanol:heptane (1:1, 8 mL) were separatedusing a 5×50 cm Chiralpak AD column at room temperature using anisopropanol:heptane (2:8) mobile phase with UV detection at 220 nM. Themost polar component (−ve sign of rotation) was obtained as a whitesolid (172 mg).

Example 197N-((1R,2R)-2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using (1R,2R)-2-amino-cyclohexanol hydrochloride(1:1) instead of 2-aminoethyl isopropylether, to the title compound (240mg, 91%) which was obtained as a white solid. MS: m/e=406.2 [M−H]⁻.

Example 198N-((1S,2S)-2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using (1S,2S)-2-amino-cyclohexanol hydrochloride(1:1) instead of 2-aminoethyl isopropylether, to the title compound (240mg, 91%) which was obtained as a white solid. MS: m/e=408.3 [M+H]⁺.

Example 199 N-((1S,2R) and(1R,2S)-2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (800 mg, 2.58mmol) was converted, using rac-cis-2-amino-cyclohexanol hydrochloride(1:1) instead of 2-aminoethyl isopropylether, to the title compound (995mg, 95%) which was obtained as a white solid. MS: m/e=406.2 [M−H]⁻.

Example 200N-(2-Hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 2-amino cyclopentanol instead of 2-aminoethylisopropylether, to the title compound (80 mg, 31%) which was obtained asa white solid. MS: m/e=494.2 [M+H]⁺.

Example 201N-(2-Hydroxy-1-hydroxymethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 2-amino-1,3-propandiol instead of2-aminoethyl isopropylether, to the title compound (215 mg, 87%) whichwas obtained as a colourless oil. MS: m/e=384.0 [M+H]⁺.

Example 2026-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N—(S)-tetrahydro-furan-3-yl-nicotinamide

As described for example 168,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(200 mg, 0.65 mmol) was converted, instead of6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinicacid methyl ester, was converted, using (S)-tetrahydrofuran-3-aminehydrochloride instead of 2,2,2-trifluoroethylamine, to the titlecompound (121 mg, 52%) which was obtained as a white solid. MS:m/e=380.1 [M+H]⁺.

Example 203N-((1R,2S)-2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamideorN-((1S,2R)-2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

The stereoisomers N-((1S,2R) and(1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(example 199, 910 mg) in ethanol:heptane (1:1, 8 mL) were separatedusing a 5×50 cm Chiralpak AD column at room temperature using anethanol:heptane (3:7) mobile phase with UV detection at 220 nM. Theleast polar component (+ve sign of rotation) was obtained as a whitesolid (270 mg).

Example 204N-((1S,2R)-2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamideorN-((1R,2S)-2-Hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

The stereoisomers N-((1S,2R) and(1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(example 199, 910 mg) in ethanol:heptane (1:1, 8 mL) were separatedusing a 5×50 cm Chiralpak AD column at room temperature using anethanol:heptane (3:7) mobile phase with UV detection at 220 nM. The mostpolar component (−ve sign of rotation) was obtained as a white solid(320 mg).

Example 205N-(2-Acetylamino-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using N-acetylethylendiamine instead of2-aminoethyl isopropylether, to the title compound (170 mg, 67%) whichwas obtained as a white solid. MS: m/e=395.1 [M+H]⁺.

Example 206N—((S)-1-Hydroxymethyl-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using L-valinol instead of 2-aminoethylisopropylether, to the title compound (220 mg, 86%) which was obtainedas a white solid. MS: m/e=394.2 [M−H]⁻.

Example 207N—((S)-1-Hydroxymethyl-3-methyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using (R)-(−)-leucinol instead of 2-aminoethylisopropylether, to the title compound (130 mg, 49%) which was obtainedas a white solid. MS: m/e=408.4 [M−H]⁻.

Example 208N—((S)-1-Hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using (S)-(+)-2-amino-1-butanol instead of2-aminoethyl isopropylether, to the title compound (210 mg, 85%) whichwas obtained as a white solid. MS: m/e=380.2 [M−H]⁻.

Example 209N—((R)-1-Hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 208,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using (R)-(+)-2-amino-1-butanol instead of(S)-(+)-2-amino-1-butanol, to the title compound (210 mg, 85%) which wasobtained as a white solid. MS: m/e=380.2 [M−H]⁻.

Example 210N-((1R,2S)-2-Hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamideorN-((1S,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (800 mg, 2.58mmol) was converted, using rac cis-2-amino cyclopentanol hydrochlorideinstead of 2-aminoethyl isopropylether, to the title compound (830 mg,82%) which was obtained as a white solid. MS: m/e=392.1 [M−H]⁻.

The stereoisomers N-((1R,2S) and(1S,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(750 mg) in ethanol (9 mL) were separated using a 5×50 cm Chiralpak ADcolumn at room temperature using an ethanol:heptane (3:7) mobile phasewith UV detection at 220 nM. The least polar component (−ve sign ofrotation) was obtained as a white solid (210 mg).

Example 211N-((1S,2R)-2-Hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamideorN-((1R,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (800 mg, 2.58mmol) was converted, using rac cis-2-amino cyclopentanol hydrochlorideinstead of 2-aminoethyl isopropylether, to the title compound (830 mg,82%) which was obtained as a white solid. MS: m/e=392.1 [M−H]⁻.

The stereoisomers N-((1R,2S) and(1S,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(750 mg) in ethanol (9 mL) were separated using a 5×50 cm Chiralpak ADcolumn at room temperature using an ethanol:heptane (3:7) mobile phasewith UV detection at 220 nM. The most polar component (−ve sign ofrotation) was obtained as a white solid (400 mg).

Example 212N-((1S,2S)-2-Hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamideorN-((1R,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (800 mg, 2.58mmol) was converted, using rac trans-2-amino cyclopentanol hydrochlorideinstead of 2-aminoethyl isopropylether, to the title compound (820 mg,81%) which was obtained as a white solid. MS: m/e=392.2 [M−H]⁻.

The stereoisomers N-((1S,2S) and(1R,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(750 mg) in ethanol (9 mL) were separated using a 5×50 cm Chiralpak ADcolumn at room temperature using an ethanol:heptane (3:7) mobile phasewith UV detection at 220 nM. The least polar component (−ve sign ofrotation) was obtained as a white solid (310 mg).

Example 213N-((1R,2R)-2-Hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamideorN-((1S,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (800 mg, 2.58mmol) was converted, using rac trans-2-amino cyclopentanol hydrochlorideinstead of 2-aminoethyl isopropylether, to the title compound (820 mg,81%) which was obtained as a white solid. MS: m/e=392.2 [M−H]⁻.

The stereoisomers N-((1S,2S) and(1R,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(750 mg) in ethanol (9 mL) were separated using a 5×50 cm Chiralpak ADcolumn at room temperature using an ethanol:heptane (3:7) mobile phasewith UV detection at 220 nM. The most polar component (+ve sign ofrotation) was obtained as a white solid (310 mg).

Example 2146-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-[2-(2-oxo-imidazolidin-1-yl)-ethyl]-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using (1-(2-aminoethyl)imidazoidin-2-one instead of2-aminoethyl isopropylether, to the title compound (175 mg, 64%) whichwas obtained as a white solid. MS: m/e=422.1 [M+H]⁺.

Example 215N-(3-Hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 4-amino-2-butanol instead of 2-aminoethylisopropylether, to the title compound (221 mg, 90%) which was obtainedas a white solid. MS: m/e=380.3 [M−H]⁻.

Example 2163-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-azetidine-1-carboxylicacid tert-butyl ester

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 3-amino-1-N-Boc-azetidine instead of2-aminoethyl isopropylether, to the title compound (257 mg, 86%) whichwas obtained as a white solid. MS: m/e=463.3 [M−H]⁻.

Example 217(2-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using N-Boc-ethylenediamine instead of 2-aminoethylisopropylether, to the title compound (261 mg, 90%) which was obtainedas a white solid. MS: m/e=511.5 [M+OAc]⁻.

Example 218N-(2,3-Dihydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using (R,S)-3-amino-1,2-propandiol instead of2-aminoethyl isopropylether, to the title compound (91 mg, 37%) whichwas obtained as a white solid. MS: m/e=382.3 [M−H]⁻.

Example 219N-(3-Hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 3-amino-1-propanol instead of 2-aminoethylisopropylether, to the title compound (200 mg, 84%) which was obtainedas a colourless oil. MS: m/e=368.0 [M+H]⁺.

Example 220N-(4-Hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid methyl ester (180 mg, 0.55 mmol) and 4-amino-1-butanol (59 mg, 0.66mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene(23 mg, 0.17 mmol) and the reaction stirred under argon for 6 h at roomtemperature. Saturated aqueous sodium bicarbonate (1 mL) was then addedand the resulting mixture was extracted with ethyl acetate (3×5 mL). Thecombined organic extracts were then dried over sodium sulfate andevaporated. Purification by chromatography (SiO₂,dichloromethane:methanol=100:0 to 9:1) afforded the title compound (78mg, 37%) which was obtained as a white solid. MS: m/e=382.2 [M+H]⁺.

Example 221N-(5-Hydroxy-pentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 220,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(180 mg, 0.55 mmol) was converted, using 5-amino-1-pentanol instead of3-amino-1-propanol, to the title compound (31 mg, 14%) which wasobtained as a white solid. MS: m/e=396.1 [M+H]⁺.

Example 222N-(6-Hydroxy-hexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 220,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(180 mg, 0.55 mmol) was converted, using 6-amino-1-hexanol instead of3-amino-1-propanol, to the title compound (45 mg, 20%) which wasobtained as a white solid. MS: m/e=410.3 [M+H]⁺.

Example 223(3-Hydroxy-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 220,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(120 mg, 0.37 mmol) was converted, using 3-pyrrolidinol instead of3-amino-1-propanol, to the title compound (122 mg, 87%) which wasobtained as a colourless oil. MS: m/e=380.3 [M+H]⁺.

Example 224((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 220,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(120 mg, 0.37 mmol) was converted, using L-prolinol instead of3-amino-1-propanol, to the title compound (122 mg, 84%) which wasobtained as a colourless oil. MS: m/e=394.1 [M+H]⁺.

Example 225((R)-2-Hydroxymethyl-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 223,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(120 mg, 0.37 mmol) was converted, using D-prolinol instead ofL-prolinol, to the title compound (139 mg, 96%) which was obtained as acolourless oil. MS: m/e=394.1 [M+H]′.

Example 226N-(3-Benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (300 mg, 0.97mmol) was converted, using rac 3-benzyloxy-cyclobutylamine instead of2-aminoethyl isopropylether, to the title compound (350 mg, 43%) whichwas obtained as a white solid. MS: m/e=470.2 [M+H]⁺.

Example 227[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-methyl-pyrrolidin-1-yl)-methanone

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted, using 2-methyl-pyrrolidine instead of 2-aminoethylisopropylether, to the title compound (240 mg, 99%) which was obtainedas a colourless. MS: m/e=378.3 [M+H]⁺.

Example 228[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-pyrrolidin-1-yl-methanone

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted, using pyrrolidine instead of 2-aminoethylisopropylether, to the title compound (229 mg, 98%) which was obtainedas a colourless. MS: m/e=364.3 [M+H]′.

Example 229(S)-2-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionicacid methyl ester

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (111 mg, 0.36mmol) was converted, using L-phenylalanine methylester hydrochlorideinstead of 2-aminoethyl isopropylether, to the title compound (148 mg,88%) which was obtained as a white solid. MS: m/e=470.1 [M−H]⁻.

Example 230 (cis ortrans)-N-(3-Benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

The stereoisomersN-(3-benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide(example 228, 350 mg) in ethanol (9 mL) were separated using a 5×50 cmChiralpak AD column at room temperature using an ethanol:heptane (3:7)mobile phase with UV detection at 220 nM. The least polar component (−vesign of rotation) was obtained as a white solid (160 mg).

Example 231(S)-2-{[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionicacid

To a suspension of(S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionicacid methyl ester (100 mg, 0.21 mmol) in THF (1 mL) and methanol (0.29mL) was added a solution of lithium hydroxide monohydrate (25.4 mg, 1.0mmol) in water (0.74 mL) added and the resulting mixture stirred at roomtemperature for 2 h. The mixture was acidified to pH 4 with HCl (1 N, 30mL) and the resulting mixture extracted with ethyl acetate. The combinedorganic layers were then washed with water and brine, dried over sodiumsulfate and evaporated to afford the title compound (92 mg, 95%) whichwas obtained as a white solid. MS: m/e=470.1 [M−H]⁻.

Example 232N-(3-Methyl-oxetan-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted, using 3-methyl-3-oxetanamine instead ofmethylamine, to the title compound (22 mg, 8%) which was obtained as awhite solid. MS: m/e=380.2 [M+H]⁺.

Example 233 Butane-1-sulfonic acid[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide

To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinicacid (100 mg, 0.32 mmol) in dichloromethane (5 mL) was addedbutane-1-sulfonic acid amide (44.2 mg, 0.32 mmol),N,N-dicyclohexylcarbodiimide (67.1 mg, 322 mmol) and4-dimethylaminopyridine (40.1 mg, 0.32 mmol). The resulting mixture wasstirred at room temperature overnight. The mixture was then filtered andthe filtrate was concentrated and purified by chromatography (SiO₂,heptane:ethyl acetate 100:0 to 0:100) to give the title compound (17 mg,12%) as a white solid. MS: m/e=428.1 [M−H]⁻.

Example 2346-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 2,2,2-trifluoro-1-methyl-ethylamine (ABCRFO7820EFA) instead of methylamine, to the title compound (66 mg, 47%)which was obtained as a light yellow solid. MS: m/e=404.5 [M−H]⁻.

Example 2356-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide

As described for example 234,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using L-2,2,2-trifluoro-1-methyl-ethylamine (ABCRAB146651) instead of 2,2,2-trifluoro-1-methyl-ethylamine, to the titlecompound (69 mg, 53%) which was obtained as an off white solid. MS:m/e=404.5 [M−H]⁻.

Example 236 Cyclopropanesulfonic acidmethyl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amidea) Cyclopropanesulfonic acid[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide

As described for example 233,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (128 mg, 0.41mmol) was converted, using cyclopropanesulfonic acid amide instead ofbutane-1-sulfonic acid amide, to the title compound (96 mg, 56%) whichwas obtained as an off white solid. MS: m/e=412.1 [M−H]⁻.

b) Cyclopropanesulfonic acidmethyl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide

To a solution of mixture of iodomethane (120 μL, 1.91 mmol),triethylamine (245 μL, 1.75 mmol) and anhydrous sodium carbonate (36.9mg, 0.35 mmol) in DMF (0.5 mL) was added cyclopropanesulfonic acid[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide(44 mg, 0.11 mmol). The reaction mixture was then heated in themicrowave for 40 min at 100° C. The mixture was then cooled andevaporated and the residue was purified by chromatography (SiO₂,heptane:ethyl acetate 2:1 to 1:1) to give the title compound (3.9 mg,9%) as a yellow solid. MS: m/e=486.3 [M+OAc]⁻.

Example 2376-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of2-aminoethyl isopropylether, to the title compound (102 mg, 41%) whichwas obtained as a white solid. MS: m/e=388.1 [M−H]⁻.

Example 2381-[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-1,2-dihydro-pyrazol-3-one

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using 3-pyrazolidinone hydrochloride instead of2-aminoethyl isopropylether, to the title compound (12 mg, 5%) which wasobtained as a white solid. MS: m/e=375.0 [M−H]⁻.

Example 239N-(1-Methyl-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 1-methylcyclopropylamine hydrochlorideinstead of methylamine, to the title compound (97 mg, 83%) which wasobtained as a white solid. MS: m/e=362.5 [M−H]⁻.

Example 240Azetidin-1-yl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using azetidine instead of methylamine, to thetitle compound (32 mg, 28%) which was obtained as a light yellow oil.MS: m/e=350.3 [M+H]′.

Example 241(3-Methoxy-azetidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 8b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 3-methoxyazetidine hydrochloride instead ofmethylamine, to the title compound (75 mg, 61%) which was obtained as alight yellow oil. MS: m/e=380.3 [M+H]⁺.

Example 242[6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiazolidin-3-yl-methanone

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65mmol) was converted, using thiazolidine instead of 2-aminoethylisopropylether, to the title compound (68 mg, 28%) which was obtained asa white solid. MS: m/e=382.2 [M+H]′.

Example 243N-(1-Cyano-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 1-amino-1-cyclopropanecarbonitrile instead of2-aminoethyl isopropylether, to the title compound (61 mg, 51%) whichwas obtained as a white solid. MS: m/e=375.2 [M+H]⁺.

Example 2446-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of2-aminoethyl isopropylether, to the title compound (110 mg, 87%) whichwas obtained as a colourless oil. MS: m/e=390.2 [M+H]⁺.

Example 2455-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine

To a stirred solution of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6mmol), N-ethyldiisopropylamine (1.04 g, 2.0 mmol) and1-hydroxybenzotriazole hydrate (40 mg, 0.3 mmol) in DMF (16 mL) atambient temperature and under argon was added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(517 mg, 1.6 mmol) followed by N-hydroxymethylacetamidine (149 mg, 2.0mmol). After 14 h the mixture was diluted with water (15 mL) andextracted with EtOAc (3×25 mL). The combined extracts were washed with10% aqueous LiCl solution (2×10 mL) then dried over sodium sulfate,filtered and concentrated. The residue was then dissolved in DMF (16 mL)and heated at 140° C. for 3 h then cooled, diluted with EtOAc (60 mL),washed with 10% aqueous LiCl (3×100 mL), then dried over sodium sulfate,filtered and concentrated. Purification by chromatography (SiO₂,heptane:ethyl acetate 8:2 to 0:1) afforded the title compound (385 mg,69%) as a yellow solid. MS: m/e=349.4 [M+H]⁺.

Example 2462-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-pyridinea) 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid hydrazide

A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester (1.0 g, 3 mmol), hydrazine (3.09 g, 62 mmol) and ethanol (1mL) was heated at 90° C. for 5 h.

The mixture was then cooled to room temperature and concentrated to givea white residue that was triturated with chloroform and filtered. Thefiltrates were concentrated to afford the title compound (743 mg, 15.1mmol) in 66% purity. This material was used directly without furtherpurification. MS: m/e=325.4 [M+H]⁺.

b)2-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-pyridine

A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acidhydrazide (300 mg, 0.6 mmol) and acetamidine hydrochloride (87 mg, 0.9mmol) in DMF (6 mL) was heated at 120° C. for 2 h. A second portion ofacetamidine hydrochloride (174 mg, 1.8 mmol) was added. After 8 h themixture was cooled to room temperature and diluted with ethylacetate (40mL). The mixture was filtered and the filtrates collected and washedwith water (3×10 mL) and brine (10 mL) then dried over sodium sulfate,filtered and concentrated. Purification by chromatography (SiO₂, 0-5%dichloromethane:methanol=100:0 to 95:5) followed by purification by HPLC(acetonitrile:water=2:8) gave the title compound (42 mg, 20%) as a whitesolid. MS: m/e=348.2 [M+H]⁺.

Example 2472-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-methylsulfanyl-pyridine

To a solution of5-bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine (300 mg,0.87 mmol) in THF (3 mL) was added n-butyllithium (1.6 M, 543.1 μL, 0.87mmol) and the resulting mixture stirred at −78° C. for 30 min. Thenmethyl disulfide (78.7 μL, 0.87 mmol) was added and the resultingmixture stirred overnight. The mixture was then evaporated. Purificationby chromatography (SiO₂, heptane:ethyl acetate 8:2 to 1:3) afforded thetitle compound (136 mg, 50%) as a light yellow oil. MS: m/e=313.1[M+H]⁺.

Example 2485-Methanesulfinyl-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine

To a solution of2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-methylsulfanyl-pyridine (70mg, 0.22 mmol) in dichloromethane (2.1 mL) was added2-benzenesulfonyl-3-phenyl-oxaziridine (58.5 mg, 0.22 mmol) and thereaction mixture was stirred overnight at room temperature. The mixturewas then evaporated. Purification by chromatography (SiO₂, heptane:ethylacetate 8:2 to 1:3) afforded the title compound (70 mg, 95%) as a whitesolid. MS: m/e=329.2 [M+H]⁺.

Example 2496-(5-Methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamidea) (E)- and/or (Z)-3-Methyl-benzaldehyde oxime

As described for example 84a, m-tolualdehyde (15.0 g, 118.6 mmol) wasconverted, instead of 2-fluorobenzaldehyde, to the title compound (16.0g, 100%) which was obtained as a yellow liquid. MS: m/e=135.0 [M]⁺.

b) (E)- and/or (Z)-3-Methyl-N-hydroxy-benzenecarboximidoyl chloride

As described for example 84b, (E)- and/or (Z)-3-methyl-benzaldehydeoxime (17.4 g, 128.7 mmol) was converted, instead of (E)- and/or(Z)-2-fluoro-benzaldehyde oxime, to the title compound (21.8 g, 100%)which was obtained as a yellow liquid. MS: m/e=169.1 [M]⁺.

c) 5-Methyl-3-m-tolyl-isoxazole-4-carboxylic acid ethyl ester

As described for example 84c, (E)- and/or(Z)-3-methyl-N-hydroxy-benzenecarboximidoyl chloride (10 g, 44.2 mmol)was converted, instead of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride, to the titlecompound (5.1 g, 47%) which was obtained as a light yellow oil. MS:m/e=246.3 [M+H]⁺.

d) (5-Methyl-3-m-tolyl-isoxazol-4-yl)-methanol

As described for example 84d, 5-methyl-3-m-tolyl-isoxazole-4-carboxylicacid ethyl ester (5.1 g, 20.8 mmol) was converted, instead of3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (3.2 g, 77%) which was obtained as a light yellowoil. MS: m/e=262.3 [M+OAc]⁻.

e) 6-(5-Methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methylester

As described for example 84e,(5-methyl-3-m-tolyl-isoxazol-4-yl)-methanol (3.2 g, 15.9 mmol) wasconverted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (1.8 g, 33%) which was obtained as a colourless oil. MS:m/e=339.3 [M+H]⁺.

f)6-(5-Methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 84f,6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(200 mg, 0.6 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine, to the title compound (190 mg, 79%) which wasobtained as a white solid. MS: m/e=408.4 [M+H]⁺.

Example 250N-Isopropyl-6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 249f,6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(200 mg, 0.6 mmol) was converted, using isopropylamine instead of4-aminotetrahydropyran, to the title compound (160 mg, 74%) which wasobtained as a white solid. MS: m/e=366.1 [M+H]⁺.

Example 2516-(5-Methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamidea) (E)- and/or (Z)-4-Methyl-benzaldehyde oxime

As described for example 249a, p-tolualdehyde (50.0 g, 408 mmol) wasconverted, instead of m-tolualdehyde, to the title compound (45.1 g,82%) which was obtained as a white solid. 1H-NMR (CDCl₃): 2.38 (s, 3H),7.20-7.25 (m, 2H), 7.45-7.50 (m, 2H), 8.12 (s, 1H), 8.40-8.60 (br s,1H).

b) (E)- and/or (Z)-4-Methyl-N-hydroxy-benzenecarboximidoyl chloride

As described for example 249b, (E)- and/or (Z)-4-methyl-benzaldehydeoxime (45.0 g, 333 mmol) was converted, instead of (E)- and/or(Z)-3-methyl-benzaldehyde oxime, to the title compound (73.2 g, 100%,77% purity) which was obtained as a yellow liquid. MS: m/e=1H-NMR(CDCl₃): 2.38 (s, 3H), 7.20-7.25 (m, 2H), 7.65-7.70 (m, 2H), 8.80-9.10(br s, 1H).

c) 5-Methyl-3-p-tolyl-isoxazole-4-carboxylic acid ethyl ester

As described for example 249c, (E)- and/or(Z)-4-methyl-N-hydroxy-benzenecarboximidoyl chloride (10 g, 45.4 mmol,77% purity) was converted, instead of E)- and/or(Z)-3-methyl-N-hydroxy-benzenecarboximidoyl chloride, to the titlecompound (12.6 g, 100%, 80% purity) which was obtained as a light yellowliquid. MS: m/e=246.2 [M+H]⁺.

d) (5-Methyl-3-p-tolyl-isoxazol-4-yl)-methanol

As described for example 249d, 5-methyl-3-p-tolyl-isoxazole-4-carboxylicacid ethyl ester (12.6 g, 51.4 mmol) was converted, instead of5-methyl-3-m-tolyl-isoxazole-4-carboxylic acid ethyl ester, to the titlecompound (3.95 g, 38%) which was obtained as a white solid. MS:m/e=204.2 [M+H]⁺.

e) 6-(5-Methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methylester

As described for example 249e,(5-methyl-3-p-tolyl-isoxazol-4-yl)-methanol (3.0 g, 14.8 mmol) wasconverted, instead of, (5-methyl-3-m-tolyl-isoxazol-4-yl)-methanol, tothe title compound (3.9 g, 78%) which was obtained as a yellow solid.MS: m/e=339.3 [M+H]⁺.

f)6-(5-Methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 249f,6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(250 mg, 0.73 mmol) was converted, instead of6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester,to the title compound (260 mg, 84%) which was obtained as a white solid.MS: m/e=408.4 [M+H]⁺.

Example 252N-Isopropyl-6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 250,6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester(250 mg, 0.73 mmol) was converted, instead of6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester,to the title compound (210 mg, 78%) which was obtained as a white solid.MS: m/e=366.3 [M+H]⁺.

Example 2536-[3-(2-Fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamidea) (E)- and/or (Z)-2-Fluoro-4-methyl-benzaldehyde oxime

As described for example 84a, 2-fluoro-4-methyl-benzaldehyde (25.0 g,172 mmol) was converted, instead of 2-fluorobenzaldehyde, to the titlecompound (26.4 g, 100%) which was obtained as a white solid. MS:m/e=154.0 [M+H]⁺.

b) (E)- and/or (Z)-2-Fluoro-4-methyl-N-hydroxy-benzenecarboximidoylchloride

As described for example 84b, (E)- and/or(Z)-2-fluoro-4-methyl-benzaldehyde oxime (26.3 g, 172 mmol) wasconverted, instead of (E)- and/or (Z)-2-fluoro-benzaldehyde oxime, tothe title compound (37.2 g, 100%, purity 87%) which was obtained as awhite solid. MS: m/e=187.0 [M]⁺.

c) 3-(2-Fluoro-4-methyl-phenyl)-5-methyl-isoxazole-4-carboxylic acidethyl ester

As described for example 84c, (E)- and/or(Z)-2-fluoro-4-methyl-N-hydroxy-benzenecarboximidoyl chloride (18.5 g,85.6 mmol) was converted, instead of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride, to the titlecompound (18.8 g, 83%) which was obtained as a light yellow oil. MS:m/e=264.0 [M+H]⁺.

d) [3-(2-Fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 84d,3-(2-fluoro-4-methyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethylester (18.5 g, 70.3 mmol) was converted, instead of3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (15.5 g, 100%) which was obtained as a light yellowoil. MS: m/e=280.1 [M+OAc]⁻.

e)6-[3-(2-Fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester

As described for example 84e,[3-(2-fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-yl]-methanol (6.64 g,30 mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (6.52 g, 61%) which was obtained as a yellow solid. MS:m/e=357.1 [M+H]⁺.

f)6-[3-(2-Fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 84f,6-[3-(2-fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (200 mg, 0.56 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine,to the title compound (90 mg, 42%) which was obtained as a white solid.MS: m/e=384.3 [M+H]⁺.

Example 2546-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide

As described for example 191,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(100 mg, 0.29 mmol) was converted, instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, using2-amino-2-methyl-1-propanol instead of 2-aminoethyl isopropylether, tothe title compound (37 mg, 30%) which was obtained as a white solid. MS:m/e=416.2 [M+H]⁺.

Example 2556-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

As described for example 254,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(100 mg, 0.29 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamineinstead of 2-amino-2-methyl-1-propanol, to the title compound (90 mg,73%) which was obtained as a white solid. MS: m/e=424.2 [M+H]⁺.

Example 2566-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide

As described for example 254,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(100 mg, 0.29 mmol) was converted, using D-alaninol instead of2-amino-2-methyl-1-propanol, to the title compound (100 mg, 94%) whichwas obtained as a white solid. MS: m/e=402.2 [M+H]⁺.

Example 2576-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide

As described for example 254,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(100 mg, 0.29 mmol) was converted, using L-alaninol instead of2-amino-2-methyl-1-propanol, to the title compound (110 mg, 94%) whichwas obtained as a white solid. MS: m/e=402.3 [M+H]⁺.

Example 2586-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide

As described for example 254,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(100 mg, 0.29 mmol) was converted, usingL-2,2,2-trifluoro-1-methyl-ethylamine (ABCR AB146651) instead of2-amino-2-methyl-1-propanol, to the title compound (91 mg, 71%) whichwas obtained as a white solid. MS: m/e=440.2 [M+H]⁺.

Example 2596-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamideor6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide

As described for example 254,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(300 mg, 0.87 mmol) was converted, using rac trans-2-amino cyclopentanolhydrochloride instead of 2-amino-2-methyl-1-propanol, to the titlecompound (300 mg, 80%) which was obtained as a white solid. MS:m/e=428.2 [M+H]⁺.

The stereoisomers N-((1S,2S) and(1R,2R)-6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-2-hydroxy-cyclopentyl)-nicotinamide(300 mg) in ethanol:heptane (1:1, 8 mL) were separated using a 5×50 cmChiralpak AD column at room temperature using an isopropanol:heptane(3:7) mobile phase with UV detection at 220 nM. The least polarcomponent (−ve sign of rotation) was obtained as a white solid (100 mg).

Example 2606-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamideor6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide

As described for example 254,6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid(300 mg, 0.87 mmol) was converted, using rac trans-2-amino cyclopentanolhydrochloride instead of 2-amino-2-methyl-1-propanol, to the titlecompound (300 mg, 80%) which was obtained as a white solid. MS:m/e=428.2 [M+H]⁺.

The stereoisomers N-((1S,2S) and(1R,2R)-6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-2-hydroxy-cyclopentyl)-nicotinamide(300 mg) in ethanol:heptane (1:1, 8 mL) were separated using a 5×50 cmChiralpak AD column at room temperature using an isopropanol:heptane(3:7) mobile phase with UV detection at 220 nM. The most polar component(+ve sign of rotation) was obtained as a white solid (110 mg).

Example 2616-[3-(2,3-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamidea) (E)- and/or (Z)-2,3-Difluoro-benzaldehyde oxime

As described for example 84a, 2,3-difluorobenzaldehyde (25.0 g, 172mmol) was converted, instead of 2-fluorobenzaldehyde, to the titlecompound (26.3 g, 97%) which was obtained as a white solid. 1H-NMR(CDCl₃): 7.05-7.30 (m, 2H), 7.45-7.55 (m, 1H), 8.35 (s, 1H), 8.55 (s,1H).

b) (E)- and/or (Z)-2,3-Difluoro-N-hydroxy-benzenecarboximidoyl chloride

As described for example 84b, (E)- and/or (Z)-2,3-difluoro-benzaldehydeoxime (26.3 g, 167 mmol) was converted, instead of (E)- and/or(Z)-2-fluoro-benzaldehyde oxime, to the title compound (41.4 g, 100%,purity 77%) which was obtained as a yellow liquid. 1H-NMR (CDCl₃):7.10-7.30 (m, 2H), 7.40-7.50 (m, 1H), 8.05 (s, 1H).

c) 3-(2,3-Difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethylester

As described for example 84c, (E)- and/or(Z)-2,3-difluoro-N-hydroxy-benzenecarboximidoyl chloride (20 g, 81 mmol,purity 77%) was converted, instead of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride, to the titlecompound (17.8 g, 83%) which was obtained as a light yellow liquid. MS:m/e=268.2 [M+H]⁺.

d) [3-(2,3-Difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 84d,3-(2,3-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester(16.0 g, 59.9 mmol) was converted, instead of3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (4.7 g, 35%) which was obtained as a yellow oil. MS:m/e=226.2 [M+H]⁺.

e) 6-[3-(2,3-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester

As described for example 84e,[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (4.70 g, 21mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (3.47 g, 46%) which was obtained as a light yellow solid. MS:m/e=361.1 [M+H]⁺.

f)6-[3-(2,3-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 84f,6-[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, to the title compound (120 mg, 56%) which was obtained asa colourless oil. MS: m/e=386.5 [M−H]⁻.

Example 2626-[3-(2,3-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 261f,6-[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using4-aminotetrahydropyran instead of isopropylamine, to the title compound(190 mg, 80%) which was obtained as a white solid. MS: m/e=430.3 [M+H]⁺.

Example 2636-[3-(2,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamidea) (E)- and/or (Z)-2,4-Difluoro-benzaldehyde oxime

As described for example 84a, 2,4-difluorobenzaldehyde (50.0 g, 344mmol) was converted, instead of 2-fluorobenzaldehyde, to the titlecompound (43.8 g, 81%) which was obtained as a white solid. MS:m/e=156.9 [M−H]⁻.

b) (E)- and/or (Z)-2,4-Difluoro-N-hydroxy-benzenecarboximiodyl chloride

As described for example 84b, (E)- and/or (Z)-2,4-difluoro-benzaldehydeoxime (44.1 g, 281 mmol) was converted, instead of (E)- and/or(Z)-2-fluoro-benzaldehyde oxime, to the title compound (58.8 g, 100%,purity 92%) which was obtained as a yellow solid. MS: m/e=191.1 [M]⁺.

c) 3-(2,4-Difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethylester

As described for example 84c, (E)- and/or(Z)-2,4-difluoro-N-hydroxy-benzenecarboximiodyl chloride (58.8 g, 281mmol, purity 77%) was converted, instead of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride, to the titlecompound (62.2 g, purity 84%) which was obtained as a light brown oil.MS: m/e=268.2 [M+H]⁺.

d) [3-(2,4-Difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 84d,3-(2,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester(61.9 g, 232 mmol) was converted, instead of3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (20.3 g, 39%) which was obtained as a light brownsolid. MS: m/e=284.1 [M+OAc]⁻.

e) 6-[3-(2,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester

As described for example 84e,[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (6.0 g, 26.6mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (5.77 g, 60%) which was obtained as a white solid. MS:m/e=361.1 [M+H]⁺.

f)6-[3-(2,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 84f,6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, to the title compound (201 mg, 93%) which was obtained asa colourless oil. MS: m/e=386.1 [M−H]⁻.

Example 2646-[3-(2,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 263f,6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using4-aminotetrahydropyran instead of isopropylamine, to the title compound(219 mg, 92%) which was obtained as a white solid. MS: m/e=428.1 [M−H]⁻.

Example 2656-[3-(2,5-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamidea) 2,5-Difluoro-benzaldehyde oxime

As described for example 84a, 2,5-difluorobenzaldehyde (25.0 g, 172mmol) was converted, instead of 2-fluorobenzaldehyde, to the titlecompound (26.6 g, 98%) which was obtained as a white solid. 1H-NMR(CDCl₃): 7.05-7.10 (m, 2H), 7.45-7.50 (m, 1H), 8.35 (s, 1H), 8.30-8.60(br s, 1H).

b) (E)- and/or (Z)-2,5-Difluoro-N-hydroxy-benzenecarboximiodyl chloride

As described for example 84b, (E)- and/or (Z)-2,5-difluoro-benzaldehydeoxime (26.6 g, 169 mmol) was converted, instead of (E)- and/or(Z)-2-fluoro-benzaldehyde oxime, to the title compound (41.8 g, 100%,purity 78%) which was obtained as a yellow solid. 1H-NMR (CDCl₃):7.05-7.10 (m, 2H), 7.35-7.40 (m, 1H), 8.05 (s, 1H).

c) 3-(2,5-Difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethylester

As described for example 84c, (E)- and/or(Z)-2,5-difluoro-N-hydroxy-benzenecarboximiodyl chloride (20 g, 81 mmol,purity 78%) was converted, instead of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride, to the titlecompound (20.2 g, 93%) which was obtained as a yellow liquid. MS:m/e=268.2 [M+H]⁺.

d) [3-(2,5-Difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 84d,3-(2,5-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester(18 g, 67.4 mmol) was converted, instead of3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (3.25 g, 21%) which was obtained as a yellow oil. MS:m/e=226.2 [M+H]⁺.

e) 6-[3-(2,5-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester

As described for example 84e,[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.2 g, 14.2mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (1.18 g, 23%) which was obtained as a white solid. MS:m/e=360.9 [M+H]⁺.

f)6-[3-(2,5-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 84f,6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, to the title compound (200 mg, 93%) which was obtained asa colourless oil. MS: m/e=386.5 [M−H]⁻.

Example 2666-[3-(2,5-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 265f,6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using4-aminotetrahydropyran instead of isopropylamine, to the title compound(170 mg, 71%) which was obtained as a colourless oil. MS: m/e=430.5[M+H]⁺.

Example 2676-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide

As described for example 125f,6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using2-amino-2-methyl-1-propanol instead of 2,2,2-trifluoroethylamine, to thetitle compound (120 mg, 50%) which was obtained as a colourless oil. MS:m/e=418.3 [M+H]′.

Example 2686-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2-dimethyl-propyl)-nicotinamide

As described for example 125f,6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using3-amino-2,2-dimethyl-1-propanol instead of 2,2,2-trifluoroethylamine, tothe title compound (120 mg, 48%) which was obtained as a colourless oil.MS: m/e=432.2 [M+H]⁺.

Example 2696-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-2-methyl-propyl)-nicotinamide

As described for example 125f,6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester (200 mg, 0.56 mmol) was converted, using1-amino-2-methyl-propan-2-ol instead of 2,2,2-trifluoroethylamine, tothe title compound (40 mg, 17%) which was obtained as a colourless oil.MS: m/e=418.3 [M+H]⁺.

Example 2706-[3-(4-Chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamidea) (E)- and/or (Z)-4-Chloro-2-fluoro-benzaldehyde oxime

As described for example 84a, 4-chloro-2-fluorobenzaldehyde (5.2 g, 32.5mmol) was converted, instead of 2-fluorobenzaldehyde, to the titlecompound (4.7 g, 83%) which was obtained as a white solid. MS: m/e=172.0[M−H]⁻.

b) (E)- and/or (Z)-4-Chloro-2-fluoro-N-hydroxy-benzenecarboximiodylchloride

As described for example 84b, (E)- and/or(Z)-4-chloro-2-fluoro-benzaldehyde oxime (4.7 g, 27.1 mmol) wasconverted, instead of (E)- and/or (Z)-2-fluoro-benzaldehyde oxime, tothe title compound (7.53 g, 100%, purity 75%) which was obtained as alight yellow solid. 1H-NMR (CDCl₃): 7.10-7.25 (m, 2H), 7.50-7.60 (m,1H), 8.05 (s, 1H).

c) 3-(4-Chloro-2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acidethyl ester

As described for example 84c, (E)- and/or(Z)-4-chloro-2-fluoro-N-hydroxy-benzenecarboximiodyl chloride (5.0 g, 18mmol, purity 75%) was converted, instead of (E)- and/or(Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride, to the titlecompound (6.5 g, 85%) which was obtained as a yellow liquid. MS:m/e=283.9 [M+H]⁺.

d) [3-(4-Chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 84d,3-(4-chloro-2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethylester (6.3 g, 20 mmol) was converted, instead of3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (2.1 g, 43%) which was obtained as an orange solid.MS: m/e=242.2 [M+H]⁺.

e)6-[3-(4-Chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester

As described for example 84e,[3-(4-chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (500 mg,2.07 mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (410 mg, 53%) which was obtained as a colourless oil. MS:m/e=377.2 [M+H]⁺.

f)6-[3-(4-Chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 84f,6-[3-(4-chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (100 mg, 0.27 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, to the title compound (80 mg, 75%) which was obtained as alight yellow oil. MS: m/e=386.5 [M−H]⁻.

Example 271 6-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinicacid methyl ester a) (E)- and/or (Z)-Pyridine-2-carbaldehyde oxime

As described for example 84a, 2-pyridinecarboxaldehyde (53.6 g, 500mmol) was converted, instead of 2-fluorobenzaldehyde, to the titlecompound (47.7 g, 78%) which was obtained as an off white solid. MS:m/e=123.3 [M+H]⁺.

b) 5-Methyl-3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester

To a suspension of N-chlorosuccinimide (6.0 g, 33 mmol) in chloroform(20 mL) was added pyridine (0.26 mL, 3.3 mmol) and a solution of (E)-and/or (Z)-pyridine-2-carbaldehyde oxime (4.0 g, 33 mmol) in chloroform(103 mL) during 15 min at ambient temperature. After stirring for 30 minat this temperature a solution of ethyl(E)-3-(1-pyrrolidino)-2-butenoate (6.0 g, 33 mmol) in chloroform (4 mL)was added. The resulting suspension was warmed to 50° C. and a solutionof triethylamine (12 mL, 86 mmol) in chloroform (10 mL) was addeddropwise over a period of 1 h. Stirring was continued for 0.5 h at 50°C. and for 30 h at room temperature. The dark brown solution was washedwith water (100 mL) and the aqueous layers were extracted withdichloromethane (50 mL) and dried over sodium sulfate and evaporated.Purification by chromatography (SiO₂, heptane:ethyl acetate 8:2 to 1:1)afforded the title compound (4.43 g, 58%) as a yellow oil. MS: m/e=233.3[M+H]⁺.

c) (5-Methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol

To a solution of 5-methyl-3-pyridin-2-yl-isoxazole-4-carboxylic acidethyl ester (4.1 g, 18 mmol) in THF (229 mL) at 0° C. was added lithiumaluminum hydride (367 mg, 10 mmol). And the resulting mixture stirredfor 1 h at room temperature. Water (1.9 mL) was added carefully followedby aqueous sodium hydroxide (15%, 1.9 mL) and water (0.54 mL). Theresulting suspension was stirred for 15 min at ambient temperature andfiltered over Hyflo®. Concentration and trituration with heptaneafforded the title compound (2.88 g, 86%) as a light yellow solid. MS:m/e=191.3 [M+H]⁺.

d) 6-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester

As described for example 84e,(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (2.83 g, 14.9 mmol) wasconverted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (1.63 g, 34%) which was obtained as a white solid. MS:m/e=326.3 [M+H]⁺.

Example 2726-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 84f,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine, to the title compound (93 mg, 79%) which wasobtained as a white solid. MS: m/e=395.0 [M+H]⁺.

Example 273N-Isopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using isopropylamine instead of4-aminotetrahydropyran, to the title compound (97 mg, 92%) which wasobtained as a white solid. MS: m/e=353.4 [M+H]⁺.

Example 274[6-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using morpholine instead of4-aminotetrahydropyran, to the title compound (90 mg, 79%) which wasobtained as a white solid. MS: m/e=381.3 [M+H]⁺.

Example 2756-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamineinstead of 4-aminotetrahydropyran, to the title compound (115 mg, 98%)which was obtained as a white solid. MS: m/e=393.4 [M+H]⁺.

Example 276(1,1-Dioxo-1,6-thiomorpholin-4-yl)-[6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using thiomorpholine1,1-dioxide instead of 4-aminotetrahydropyran, to the title compound (41mg, 32%) which was obtained as a white solid. MS: m/e=429.3 [M+H]⁺.

Example 277N-Cyclopropylmethyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using aminomethylcyclopropaneinstead of 4-aminotetrahydropyran, to the title compound (93 mg, 85%)which was obtained as an off white solid. MS: m/e=365.4 [M+H]⁺.

Example 278N-Cyclopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using cyclopropylamine insteadof 4-aminotetrahydropyran, to the title compound (86 mg, 82%) which wasobtained as a white solid. MS: m/e=365.4 [M+H]⁺.

Example 279Methyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using methylamine (2 M solutionin THF) instead of 4-aminotetrahydropyran, to the title compound (35 mg,36%) which was obtained as a white solid. MS: m/e=325.3 [M+H]⁺.

Example 280Ethyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using ethylamine (2 M solutionin THF) instead of 4-aminotetrahydropyran, to the title compound (79 mg,78%) which was obtained as a white solid. MS: m/e=339.3 [M+H]′.

Example 281(2-Hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to thetitle compound (25 mg, 22%) which was obtained as a white solid. MS:m/e=383.3 [M+H]⁺.

Example 282[6-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone

As described for example 272,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (97.6 mg, 0.3 mmol) was converted, using thiomorpholine instead of4-aminotetrahydropyran, to the title compound (106 mg, 89%) which wasobtained as a white solid. MS: m/e=397.1 [M+H]⁺.

Example 283 6-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinicacid

To a suspension of6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (330 mg, 1.0 mmol) in THF (3 mL) and methanol (3 mL) was added asolution of lithium hydroxide monohydrate (85.1 mg, 2.0 mmol) in water(3 mL) added and the resulting mixture stirred at room temperatureovernight. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) andthe resulting mixture was filtered. The solid was dried to afford thetitle compound (284 mg, 90%) which was obtained as a white solid. MS:m/e=310.5 [M−H]⁻.

Example 284(2-Hydroxy-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 98b,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (77.8mg, 0.25 mmol) was converted, instead of6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,using aminoethanol instead of 2,2,2-trifluoroethylamine, to the titlecompound (21 mg, 24%) which was obtained as a white solid. MS: m/e=355.0[M+H]⁺.

Example 285(2-Methoxy-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 284,6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (77.8mg, 0.25 mmol) was converted, using 2-methoxyethylamine instead ofaminoethanol, to the title compound (21 mg, 24%) which was obtained as awhite solid. MS: m/e=369.1 [M+H]⁺.

Example 2866-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester a) 5-Fluoro-pyridine-2-carbaldehyde oxime

To a solution of 5-fluoro-2-formylpyridine (5.0 g, 41 mmol) andhydroxylamine hydrochloride (3.06 g, 44 mmol) in ethanol (3.2 mL) andwater (9.6 mL) was added ice (18.6 g). Then a solution of NaOH (4.0 g,100 mmol) in water (4.6 mL) was added dropwise over 10 min keeping thetemperature between −5° C. and 5° C. The reaction mixture was thenstirred at room temperature for 30 min. Then HCl (4 N) was added toacidify the mixture and the resulting precipitate was filtered off andwashed with water to afford the title compound (4.41 g, 79%) as a lightbrown solid. MS: m/e=141.0 [M+H]⁺.

b) 3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethylester

To a suspension of N-chlorosuccinimide (4.63 g, 35 mmol) in chloroform(21 mL) was added pyridine (0.28 mL, 3.5 mmol) and a solution of5-fluoro-pyridine-2-carbaldehyde oxime (4.86 g, 35 mmol) in chloroform(110 mL) during 15 min at room temperature. After stirring for 30 min atthis temperature a solution of ethyl (E)-3-(1-pyrrolidino)-2-butenoate(6.36 g, 35 mmol) in chloroform (4.4 mL) was added. The resultingsuspension was warmed to 50° C. and a solution of triethylamine (4.83mL, 35 mmol) in chloroform (4.4 mL) was added dropwise over a period of30 min. Stirring was continued for 1.5 h at 50° C. and then cooled toambient temperature. The solution was then diluted with ice-water (200mL) and the aqueous layers were extracted with dichloromethane (50 mL)and dried over sodium sulfate and evaporation to give a dark brown oil.Purification by chromatography (SiO₂, heptane:ethyl acetate=100:0 to20:80) afforded the title compound (5.83 g, 67%) as yellow oil. MS:m/e=251.1 [M+H]⁺.

c) [3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol

To a solution of3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethylester (2.5 g, 10 mmol) in dry THF (34 mL), cooled to 0° C., was addedlithiumaluminumhydride (209 mg, 2.3 mmol) portionwise. After allowing towarm up to room temperature over 1 h, the mixture was cooled to 0° C.and water (0.2 mL) was added carefully followed by aqueous sodiumhydroxide (15%, 0.2 mL) and water (0.6 mL). The resulting suspension wasstirred for 4 h at ambient temperature and filtered over Hyflo®. Thefiltrate was then concentrated and purification by chromatography (SiO₂,heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (1.47g, 71%) as a light yellow solid. MS: m/e=209.1 [M+H]⁺.

d) 6-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester

As described for example 84e,[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (600 mg, 2.8mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (210 mg, 21%) which was obtained as a white solid. MS:m/e=344.1 [M+H]⁺.

Example 2876-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid

As described for example 283,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (175 mg, 0.51 mmol) was converted, instead of6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester, to the title compound (154 mg, 92%) which was obtained as a whitesolid. MS: m/e=328.3 [M−H]⁻.

Example 2886-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 98b,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (69 mg, 0.21 mmol) was converted, instead of6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, tothe title compound (73 mg, 85%) which was obtained as a white solid. MS:m/e=413.1 [M+H]⁺.

Example 2896-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (69 mg, 0.21 mmol) was converted, using isopropylamine instead of4-aminotetrahydropyran, to the title compound (52 mg, 67%) which wasobtained as a white solid. MS: m/e=371.1 [M+H]⁺.

Example 290Cyclopropyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using cyclopropylamine instead of4-aminotetrahydropyran, to the title compound (23 mg, 41%) which wasobtained as a white solid. MS: m/e=369.0 [M+H]⁺.

Example 2916-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy](2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using 2-amino-2-methyl-1-propanolinstead of 4-aminotetrahydropyran, to the title compound (40 mg, 66%)which was obtained as a white solid. MS: m/e=401.2 [M+H]⁺.

Example 292Cyclopropylmethyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using aminomethylcyclopropaneinstead of 4-aminotetrahydropyran, to the title compound (30 mg, 52%)which was obtained as a white solid. MS: m/e=383.2 [M+H]⁺.

Example 293(1,1-Dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using thiomorpholine 1,1-dioxideinstead of 4-aminotetrahydropyran, to the title compound (41 mg, 61%)which was obtained as a white solid. MS: m/e=447.1 [M+H]⁺.

Example 2946-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using 2,2,2-trifluoroethylamineinstead of 4-aminotetrahydropyran, to the title compound (43 mg, 69%)which was obtained as a white solid. MS: m/e=411.2 [M+H]⁺.

Example 2956-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using aminoethanol instead of4-aminotetrahydropyran, to the title compound (45 mg, 80%) which wasobtained as a white solid. MS: m/e=373.1 [M+H]⁺.

Example 296{6-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using morpholine instead of4-aminotetrahydropyran, to the title compound (55 mg, 91%) which wasobtained as a colourless gum. MS: m/e=399.1 [M+H]⁺.

Example 297Ethyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (50 mg, 0.15 mmol) was converted, using ethylamine (2 M solution inTHF) instead of 4-aminotetrahydropyran, to the title compound (45 mg,83%) which was obtained as a white solid. MS: m/e=357.1 [M+H]⁺.

Example 2986-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-methyl-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (47 mg, 0.14 mmol) was converted, using methylamine (2 M solutionin THF) instead of 4-aminotetrahydropyran, to the title compound (36 mg,74%) which was obtained as a white solid. MS: m/e=343.1 [M+H]⁺.

Example 2996-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide

As described for example 288,6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (100 mg, 0.3 mmol) was converted, using L-2,2,2-trifluoroethylamineinstead of 4-aminotetrahydropyran, to the title compound (56 mg, 43%)which was obtained as a white solid. MS: m/e=423.3 [M−H]⁻.

Example 3006-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester a) 5-Chloro-pyridine-2-carbaldehyde

To a solution of 2-bromo-5-chloropyridine (14.8 g, 77 mmol) in THF (38.5mL) was added dropwise a solution of i-PrMgCl.LiCl (14% in THF, 81 mL,85 mmol) at 0-5° C. and the resulting mixture stirred at 0° C. for 1 h.Then DMF (7.7 mL, 100 mmol) was added dropwise at −5° C. and thetemperature maintained at 0° C. for 2 h. The reaction mixture was thenpoured into ice cold saturated brine (500 mL) and then extracted withethyl acetate (2×300 mL). The combined organic layers were washed withsaturated sodiumhydrogencarbonate solution, brine, dried over sodiumsulfate, filtered and evaporated. Purification by chromatography (SiO₂,heptane:ethyl acetate=1:0 to 9:1) afforded the title compound (6.24 g,57%) which was obtained as a brown solid. MS: m/e=141.0 [M]⁺.

b) (E)- and/or (Z)-5-Chloro-pyridine-2-carbaldehyde oxime

As described for example 286a, 5-chloro-pyridine-2-carbaldehyde (6.9 g,4.8 mmol) was converted, instead of 5-fluoro-2-formylpyridine, to thetitle compound (6.7 g, 89%) which was obtained as a light brown solid.MS: m/e=157.1 [M+H]⁺.

c) 3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethylester

As described for example 286b, (E)- and/or(Z)-5-chloro-pyridine-2-carbaldehyde oxime (5.6 g, 36 mmol) wasconverted, instead of 5-fluoro-pyridine-2-carbaldehyde oxime, to thetitle compound (7.7 g, 80%) which was obtained as a yellow oil. MS:m/e=267.0 [M+H]⁺.

d) [3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol

As described for example 286c,3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethylester (1.26 g, 4.7 mmol) was converted, instead of3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethylester, to the title compound (773 mg, 73%) which was obtained as an offwhite solid. MS: m/e=224.9 [M+H]⁺.

e) 6-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester

As described for example 84e,[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (726 mg, 3.2mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (578 mg, 40%) which was obtained as a white solid. MS:m/e=360.3 [M+H]⁺.

Example 3016-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 84f,6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using 4-aminotetrahydropyran instead of2,2,2-trifluoroethylamine, to the title compound (61 mg, 47%) which wasobtained as a white solid. MS: m/e=429.5 [M+H]⁺.

Example 3026-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide

As described for example 301,6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, using isopropylamineinstead of 4-aminotetrahydropyran to the title compound (83 mg, 72%)which was obtained as a white solid. MS: m/e=387.1 [M+H]⁺.

Example 3036-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropyl-nicotinamide

As described for example 301,6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, usingcyclopropylamine instead of 4-aminotetrahydropyran to the title compound(84 mg, 73%) which was obtained as a white solid. MS: m/e=385.1 [M−H]⁺.

Example 3046-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid

As described for example 283,6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (250 mg, 0.7 mmol) was converted, instead of6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester, to the title compound (83 mg, 35%) which was obtained as a whitesolid. MS: m/e=344.3 [M+H]⁻.

Example 3056-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide

As described for example 98b,6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid (56 mg, 0.16 mmol) was converted, instead of6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,using 2-amino-2-methyl-1-propanol instead of 2,2,2-trifluoroethylamine,to the title compound (36 mg, 53%) which was obtained as a white solid.MS: m/e=417.3 [M+H]⁺.

Example 3066-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropylmethyl-nicotinamide

As described for example 301,[6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, usingaminomethylcyclopropane instead of 4-aminotetrahydropyran to the titlecompound (72 mg, 60%) which was obtained as a white solid. MS: m/e=399.3[M+H]⁺.

Example 307{6-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1,6-thiomorpholin-4-yl)-methanone

As described for example 301,[6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, usingaminomethylcyclopropane instead of 4-aminotetrahydropyran to the titlecompound (69 mg, 50%) which was obtained as a white solid. MS: m/e=463.0[M]⁺.

Example 3086-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 301,[6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, using2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran to the titlecompound (64 mg, 50%) which was obtained as a white solid. MS: m/e=427.4[M+H]⁺.

Example 309{6-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone

As described for example 301,[6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, using morpholineinstead of 4-aminotetrahydropyran to the title compound (18 mg, 15%)which was obtained as a white solid. MS: m/e=415.1 [M+H]⁺.

Example 310{6-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone

As described for example 301,[6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (108 mg, 0.3 mmol) was converted, using thiomorpholineinstead of 4-aminotetrahydropyran to the title compound (76 mg, 59%)which was obtained as a white solid. MS: m/e=431.3 [M+H]⁺.

Example 3116-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide

As described for example 301,[6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinicacid methyl ester (74 mg, 0.2 mmol) was converted, using thiomorpholineinstead of 4-aminotetrahydropyran to the title compound (38 mg, 45%)which was obtained as a white solid. MS: m/e=389.1 [M+H]⁺.

Example 312 6-(5-Methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinicacid methyl ester a) (E)-4-Dimethylamino-1,1-dimethoxy-but-3-en-2-one

A mixture of N,N-dimethylformamide dimethylacetal (86.0 g, 584 mmol) andmethylglyoxal 1,1-dimethylacetal (85.6 g, 724 mmol) in isobutanol (500mL) was heated at 100° C. overnight. The mixture was then cooled andevaporated. Purification by distillation afforded the title product(49.9 g, 48%) as an orange liquid. Bp 123-124° C. at 0.9 mbar. MS:m/e=174.4 [M+H]′.

b) 4-Dimethoxymethyl-pyrimidine

A mixture of (E)-4-dimethylamino-1,1-dimethoxy-but-3-en-2-one (49.6 g,286 mmol) and formamidine acetate (44.7 g, 429 mmol) was heated at 120°C. for 4 h. After cooling to room temperature the mixture was pouredinto water and extracted with dichloromethane. The combined organicextracts were then dried over sodium sulfate, filtered and evaporated.Purification by distillation afforded the title product (31 g, 70%) as acolourless liquid. Bp 59-60° C. at 1.3 mbar. MS: m/e=155.0 [M+H]⁺.

c) Pyrimidine-4-carbaldehyde

A solution of 4-dimethoxymethyl-pyrimidine (30.6 g, 199 mmol) in water(235 mL) and concentrated sulfuric acid (2.9 g, 30 mmol) was heated at60° C. for 24 h. After cooling to room temperature the pH was set to 8with saturated aqueous sodium hydrogen carbonate solution. The mixturewas then extracted overnight in a continuous extraction (Keberle) for 48h with chloroform. The chloroform extract was then dried over sodiumsulfate, filtered and evaporated. Purification by chromatography (SiO₂,dichloromethane:methanol=1:0 to 95:5) afforded the title compound (8.1g, 26%) which was obtained as a brown oil. MS: m/e=108.0 [M]⁺.

d) Pyrimidine-4-carbaldehyde oxime

As described for example 286a, pyrimidine-4-carbaldehyde (8.1 g, 51mmol) was converted, instead of 5-fluoro-2-formylpyridine, to the titlecompound (2.2 g, 35%) which was obtained as a light brown solid. MS:m/e=124.0 [M+H]⁺.

e) 5-Methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid ethyl ester

As described for example 286b, pyrimidine-4-carbaldehyde oxime (2.2 g,18 mmol) was converted, instead of 5-fluoro-pyridine-2-carbaldehydeoxime, to the title compound (2.6 g, 63%) which was obtained as a lightbrown oil. MS: m/e=233.9 [M+H]⁺.

f) 5-Methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid

As described for example 58b,5-methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid ethyl ester (500mg, 2.1 mmol) was converted, instead of2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid methylester, to the title compound (321 mg, 73%) which was obtained as an offwhite solid. MS: m/e=204.1 [M−H]⁻.

g) (5-Methyl-3-pyrimidin-4-yl-isoxazol-4-yl)-methanol

To a solution of 5-methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid(300 mg, 1.46 mmol) in THF (4 mL) at −10° C. was added triethylamine(203 μL, 1.46 mmol) and then a solution of ethylchloroformate (139 μL,1.46 mmol) in THF (1 mL) added keeping the temperature below −5° C.After 1 h the mixture was filtered and the filtrate cooled to −10° C.and a suspension of sodiumborohydride (138 mg, 3.66 mmol) in water (1.5mL) added over 15 minutes keeping the temperature below −5° C. Themixture was then allowed to warm up to room temperature over 2 h anddiluted with aqueous sodium hydroxide (1 N) and extracted withethylacetate. The combined organic layers were then washed with waterand brine, dried over sodium sulfate and evaporated. Purification bychromatography (SiO₂, dichloromethane:methanol=9:1) afforded the titleproduct (52.5 mg, 19%) which was obtained as white solid. MS: m/e=190.0[M−H]⁻.

hi) 6-(5-Methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester

To a solution of (5-methyl-3-pyrimidin-4-yl-isoxazol-4-yl)-methanol (313mg, 1.63 mmol) in THF (20 mL) was added methyl 6-hydroxynicotinate (276mg, 1.8 mmol) and triphenylphosphine (644 mg, 2.5 mmol) at roomtemperature under an argon atmosphere. Then diethyl azodicarboxylate(˜40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixturewas stirred for 30 min at room temperature. Concentration andpurification by chromatography (SiO₂, heptane:ethyl acetate=100:0 to1:1) afforded the title compound (95 mg, 18%) as a white solid. MS:m/e=327.3 [M+H]⁺.

Or alternatively

hii) 6-(5-Methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acidmethyl ester

As described for example 84e,(5-methyl-3-pyrimidin-4-yl-isoxazol-4-yl)-methanol (139 mg, 0.73 mmol)was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (72 mg, 30%) which was obtained as a white solid. MS: m/e=327.5[M+H]⁺.

Example 313N-Isopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamidea) 6-(5-Methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid

As described for example 283,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester (53 mg, 0.16 mmol) was converted, instead of6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester, to the title compound (42 mg, 83%) which was obtained as a whitesolid. MS: m/e=311.5 [M−H]⁻.

b)N-Isopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 98b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (19mg, 0.06 mmol) was converted, instead of6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,using isopropylamine instead of 2,2,2-trifluoroethylamine, to the titlecompound (16 mg, 73%) which was obtained as a white solid. MS: m/e=354.3[M+H]⁺.

Example 314N-Cyclopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 313b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (19mg, 0.06 mmol) was converted, using cyclopropylamine instead ofisopropylamine, to the title compound (17 mg, 81%) which was obtained asa white solid. MS: m/e=352.5 [M+H]⁺.

Example 315N-(2-Hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 313b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53mg, 0.17 mmol) was converted, using cyclopropylamine instead ofisopropylamine, to the title compound (39 mg, 60%) which was obtained asa colourless gum. MS: m/e=384.1 [M+H]⁺.

Example 316[6-(5-Methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone

As described for example 313b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53mg, 0.17 mmol) was converted, using morpholine instead ofisopropylamine, to the title compound (45 mg, 70%) which was obtained asan off white foam. MS: m/e=382.4 [M+H]⁺.

Example 317N-Ethyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 313b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53mg, 0.17 mmol) was converted, using ethylamine (2 M solution in THF)instead of isopropylamine, to the title compound (45 mg, 78%) which wasobtained as a white solid. MS: m/e=340.0 [M+H]′.

Example 318N-Methyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 313b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53mg, 0.17 mmol) was converted, using methylamine (2 M solution in THF)instead of isopropylamine, to the title compound (39 mg, 70%) which wasobtained as a white solid. MS: m/e=326.3 [M+H]⁺.

Example 319[6-(5-Methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone

As described for example 313b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53mg, 0.17 mmol) was converted, using thiomorpholine instead ofisopropylamine, to the title compound (47 mg, 70%) which was obtained asa colourless gum. MS: m/e=398.1 [M+H]⁺.

Example 320N-(2-Hydroxy-ethyl)-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 313b,6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53mg, 0.17 mmol) was converted, using ethanolamine instead ofisopropylamine, to the title compound (44 mg, 73%) which was obtained asa white solid. MS: m/e=356.3 [M+H]⁺.

Example 321 N-Isopropyl-6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinamidea) 3-Phenyl-isoxazole-4-carboxylic acid methyl ester

To a mixture of (E)- and/or (Z)—N-hydroxy-benzenecarboximidoyl chloride(12.0 g, 77 mmol) and 4-nitro-benzoic-acid (E)-2-methoxycarbonyl-vinylester (9.7 g, 39 mmol) in dichloromethane (200 mL) was addedtriethylamine (20.9 mL, 150 mml) and the resulting solution stirredovernight at room temperature. The mixture was then diluted withdichloromethane (500 mL) and the organic extract removed and washed withwater, dried over sodium sulfate and evaporated. Purification bychromatography (SiO₂, heptane:ethyl acetate=100:0 to 4:1) afforded thetitle product (3.1 g, 40%) which was obtained as a light yellow oil. MS:m/e=204.2 [M+H]⁺

b) (3-Phenyl-isoxazol-4-yl)-methanol

As described for example 84d, 3-phenyl-isoxazole-4-carboxylic acidmethyl ester (2.95 g, 15 mmol) was converted, instead of3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (1.56 g, 61%) which was obtained as a light greenoil. MS: m/e=176.4 [M+H]⁺.

c) 6-(3-Phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester

As described for example 84e, (3-phenyl-isoxazol-4-yl)-methanol (700 mg,4.0 mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (288 mg, 23%) which was obtained as a light yellow gum. MS:m/e=311.3 [M+H]⁺.

d) N-Isopropyl-6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 84f,6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (67 mg,0.21 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine,to the title compound (59 mg, 81%) which was obtained as an off whitesolid. MS: m/e=338.2 [M+H]⁺.

Example 3226-(3-Phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 321d,6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (67 mg,0.21 mmol) was converted, using 4-aminotetrahydropyran instead ofisopropylamine, to the title compound (60 mg, 73%) which was obtained asan off white solid. MS: m/e=380.2 [M+H]⁺.

Example 3236-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide a)(E)- and/or (Z)-4-Fluoro-benzaldehyde oxime

As described for example 84a, 4-fluorobenzaldehyde (24.8 g, 200 mmol)was converted, instead of 2-fluorobenzaldehyde, to the title compound(23.3 g, 84%) which was obtained as a white solid. MS: m/e=139.1 [M]⁺.

b) (E)- and/or (Z)—N-Hydroxy-4-fluoro-benzenecarboximidoyl chloride

To a solution of (E)- and/or (Z)-4-fluoro-benzaldehyde oxime (100 g, 719mmol) in DMF (500 mL) was added N-chlorosuccinimide (110 g, 791 mmol)portionwise keeping the temperature below 70° C. The reaction mixturewas stirred at room temperature for 2.5 h and then extracted withtert-butyl methyl ether to afford the title compound (125 g, 100%) whichwas obtained as a yellow oil. MS: m/e=173.1 [M]⁺.

c) 3-(4-Fluoro-phenyl)-isoxazole-4-carboxylic acid ethyl ester

To a solution of (E)- and/or (Z)—N-hydroxy-4-fluoro-benzenecarboximidoylchloride (50 g, 241 mmol) in diethylether (1 L) was added a solution ofethyl 3-(N,N-dimethylamino)acrylate (87 mL, 601 mmol) and triethylamine(49 mL, 349 mmol) in diethylether (1 L). The resulting mixture was thenstirred for 14 h at room temperature and evaporated. Purification bychromatography (SiO₂, heptane:ethyl acetate=100:0 to 4:1) afforded thetitle product (50.2 g, 88%) which was obtained as a light yellow solid.MS: m/e=236.1 [M+H]⁺.

d) 3-(4-Fluoro-phenyl)-isoxazole-4-carboxylic acid

To a solution of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid ethylester (849 g, 208 mmol) in ethanol (215 mL) was added aqueous sodiumhydroxide (2 N, 161 mL, 323 mmol) and the resulting mixture stirredovernight at room temperature. The mixture was then acidified with HClsolution (4 N, 85 mL) to pH 2-3. The precipitate was then filtered offand dissolved in THF (700 mL) and then washed with saturated sodiumchloride solution. The aqueous phase was then extracted with ethylacetate and THF (1:1, 300 mL) and the combined organic phases dried oversodium sulfate and evaporated to afford the title compound (40.8 g, 94%)which was obtained as an orange solid. MS: m/e=206.1 [M−H]⁻.

e) [3-(4-Fluoro-phenyl)-isoxazol-4-yl]-methanol

To a solution of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid (40 g,193 mmol) in THF (400 mL) at −10° C. was added triethylamine (27.1 mL,193 mmol) and then a solution of ethylchloroformate (18.8 mL, 193 mmol)in THF (120 mL) added keeping the temperature below −5° C. After 1 h themixture was filtered and the filtrate cooled to −10° C. and a suspensionof sodiumborohydride (19 g, 483 mmol) in water (120 mL) added over 15minutes keeping the temperature below −5° C. The mixture was thenallowed to warm up to room temperature over 2 h and diluted with aqueoussodium hydroxide (1 N, 700 mL) and extracted with tert-butylmethylether.The combined organic layers were then washed with water and brine, driedover sodium sulfate and evaporated. Purification by chromatography(SiO₂, heptane:ethyl acetate=1:1) afforded the title product (20.1 g,54%) which was obtained as white solid. MS: m/e=194.1 [M+H]⁺.

f) 6-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methylester

As described for example 84e,[3-(4-fluoro-phenyl)-isoxazol-4-yl]-methanol (550 mg, 2.9 mmol) wasconverted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (660 mg, 71%) which was obtained as a white solid. MS:m/e=387.3 [M+OAc]⁻.

g) 6-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 84f,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(150 mg, 0.46 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine,to the title compound (160 mg, 98%) which was obtained as a white solid.MS: m/e=356.3 [M+H]⁺.

Example 3246-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 323 g,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(150 mg, 0.46 mmol) was converted, using 4-aminotetrahydropyran insteadof isopropylamine, to the title compound (160 mg, 88%) which wasobtained as a white solid. MS: m/e=398.3 [M+H]⁺.

Example 3256-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-methyl-ethyl)-nicotinamide

As described for example 220,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(100 mg, 0.31 mmol) was converted, instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester,using rac-2-amino-1-propanol instead of 3-amino-1-propanol, to the titlecompound (80 mg, 71%) which was obtained as a colourless gum. MS:m/e=372.2 [M+H]⁺.

Example 3266-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide

As described for example 325,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(60 mg, 0.18 mmol) was converted, using D-alaninol instead ofrac-2-amino-1-propanol, to the title compound (28 mg, 41%) which wasobtained as a white solid MS: m/e=372.1 [M+H]⁺.

Example 3276-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide

As described for example 325,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(60 mg, 0.18 mmol) was converted, using S-(+)-2-amino-1-propanol insteadof rac-2-amino-1-propanol, to the title compound (28 mg, 59%) which wasobtained as a white solid MS: m/e=370.3 [M−H]⁻.

Example 328N-Cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 324,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.61 mmol) was converted, using aminomethylcyclopropane insteadof 4-aminotetrahydropyran, to the title compound (70 mg, 31%) which wasobtained as a white solid. MS: m/e=368.1 [M+H]⁺.

Example 329N-Cyclopropyl-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 324,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.61 mmol) was converted, using cyclopropylamine instead of4-aminotetrahydropyran, to the title compound (60 mg, 28%) which wasobtained as a white solid. MS: m/e=343.4 [M+H]⁺.

Example 3306-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 324,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.61 mmol) was converted, using 2,2,2-trifluoroethylamineinstead of 4-aminotetrahydropyran, to the title compound (100 mg, 41%)which was obtained as a light brown solid. MS: m/e=396.1 [M+H]⁺.

Example 3316-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamidea) 6-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid

As described for example 324,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(4.0 g, 12.2 mmol) was converted, instead of6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methylester, to the title compound (3.1 g, 81%) which was obtained as a whitesolid. MS: m/e=313.3 [M−H]⁻.

b)6-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide

As described for example 191,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted, instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, using(1S,2S)-2-amino-cyclohexanol hydrochloride (1:1) instead of(1R,2R)-2-amino-cyclohexanol hydrochloride (1:1), to the title compound(180 mg, 71%) which was obtained as a white solid. MS: m/e=398.2 [M−H]⁻.

Example 3326-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamideor6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide

As described for example 331b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted, using rac-trans-2-amino-cyclohexanol hydrochloride(1:1) instead of (1S,2S)-2-amino-cyclohexanol hydrochloride (1:1), tothe title compound (110 mg, 43%) which was obtained as a colourless oil.MS: m/e=398.2 [M−H]⁻.

Example 3336-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(3,3,3-trifluoro-2-hydroxy-propyl)-nicotinamide

As described for example 325,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.61 mmol) was converted, using3-amino-1,1,1,-trifluoropropan-2-ol instead of rac-2-amino-1-propanol,to the title compound (39 mg, 15%) which was obtained as a white solidMS: m/e=426.1 [M+H]⁺.

Example 3346-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide

As described for example 325,6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.61 mmol) was converted, using 2-amino-1,3-propandiol insteadof rac-2-amino-1-propanol, to the title compound (117 mg, 49%) which wasobtained as a white solid MS: m/e=388.2 [M+H]⁺.

Example 335N-(2-Acetylamino-ethyl)-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 331b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using N-acetylethylenediamine instead of(1S,2S)-2-amino-cyclohexanol hydrochloride (1:1), to the title compound(67 mg, 53%) which was obtained as a white solid. MS: m/e=397.0 [M−H]⁻.

Example 3366-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-methoxy-ethyl)-nicotinamide

As described for example 331b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 2-methoxyethylamine instead of(1S,2S)-2-amino-cyclohexanol hydrochloride (1:1), to the title compound(89 mg, 75%) which was obtained as a light yellow solid. MS: m/e=370.0[M−H]⁻.

Example 3376-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-propyl)-nicotinamide

As described for example 331b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using R-(−)-1-amino-2-propanol instead of(1S,2S)-2-amino-cyclohexanol hydrochloride (1:1), to the title compound(75 mg, 64%) which was obtained as a light yellow solid. MS: m/e=370.0[M−H]⁻.

Example 3386-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamide

As described for example 331b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using ethanolamine instead of(1S,2S)-2-amino-cyclohexanol hydrochloride (1:1), to the title compound(85 mg, 75%) which was obtained as a white solid. MS: m/e=356.2 [M−H]⁻.

Example 3396-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(1-hydroxy-cyclopropylmethyl)-nicotinamide

As described for example 331b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32mmol) was converted, using 1-(aminomethyl)-cyclopropanol instead of(1S,2S)-2-amino-cyclohexanol hydrochloride (1:1), to the title compound(140 mg, 57%) which was obtained as a white solid. MS: m/e=384.1 [M+H]⁺.

Example 340N-(1,1-Dioxo-tetrahydro-1,6-thiophen-3-yl)-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 331b,6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64mmol) was converted, using 1,1-dioxidotetrahydrothien-3-ylamine insteadof (1S,2S)-2-amino-cyclohexanol hydrochloride (1:1), to the titlecompound (200 mg, 73%) which was obtained as a white solid. MS:m/e=432.2 [M+H]⁺.

Example 3416-[3-(4-Fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamideor6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide

The stereoisomers of6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamideor6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide(example 333, 600 mg) in ethanol:heptane (1:1, 8 mL) were separatedusing a 5×50 cm Chiralpak AD column at room temperature using anisopropanol:heptane (3:7) mobile phase with UV detection at 220 nM. Theleast polar component (−ve sign of rotation) was obtained as a whitesolid (240 mg). The most polar component (+ve sign of rotation) wasobtained as a white solid (220 mg).

Example 3426-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamidea) (E)- and/or (Z)-4-Chloro-benzaldehyde oxime

As described for example 88a, 4-chlorobenzaldehyde (25.0 g, 178 mmol)was converted, instead of 3-fluorobenzaldehyde, to the title compound(27.0 g, 97%) which was obtained as an off white solid. MS: m/e=155.1[M]⁺.

b) (E)- and/or (Z)—N-Hydroxy-4-chloro-benzenecarboximidoyl chloride

As described for example 88b, (E)- and/or (Z)-4-chloro-benzaldehydeoxime (27.0 g, 173 mmol) was converted, instead of (E)- and/or(Z)-3-fluoro-benzaldehyde oxime, to the title compound (28.4 g, 86%)which was obtained as a light yellow solid. MS: m/e=189.1 [M]⁺.

c) 3-(4-Chloro-phenyl)-isoxazole-4-carboxylic acid ethyl ester

As described for example 323c, (E)- and/or(Z)—N-hydroxy-4-chloro-benzenecarboximidoyl chloride (58.0 g, 250.3mmol) was converted, instead of (E)- and/or(Z)—N-hydroxy-4-fluoro-benzenecarboximidoyl chloride, to the titlecompound (57 g, 91%) which was obtained as a white solid. MS: m/e=252.1[M+H]⁺.

d) 3-(4-Chloro-phenyl)-isoxazole-4-carboxylic acid

As described for example 323d,3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid ethyl ester (57.0 g,226.5 mmol) was converted, instead of3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid ethyl ester, to thetitle compound (50.7 g, 92%) which was obtained as a light yellow solid.MS: m/e=222.3 [M−H]⁻.

e) [3-(4-Chloro-phenyl)-isoxazol-4-yl]-methanol

As described for example 323e,3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid (40.0 g, 178.9 mmol) wasconverted, instead of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid,to the title compound (17.3 g, 46%) which was obtained as a light greensolid. MS: m/e=210.1 [M+H]′.

f) 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methylester

As described for example 323f,[3-(4-chloro-phenyl)-isoxazol-4-yl]-methanol (8.0 g, 42 mmol) wasconverted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (9.4 g, 72%) which was obtained as a light yellow solid. MS:m/e=345.1 [M+H]⁺.

g)6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 84f,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.58 mmol) was converted, instead of[6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester, to the title compound (140 mg, 59%) which was obtained asa white solid. MS: m/e=412.1 [M+H]⁺.

Example 3436-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide

As described for example 342 g,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.58 mmol) was converted, using cyclopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (100 mg, 46%) which wasobtained as a white solid. MS: m/e=370.0 [M+H]⁺.

Example 3446-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide

As described for example 344 g,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.58 mmol) was converted, using isopropylamine instead of2,2,2-trifluoroethylamine, to the title compound (120 mg, 56%) which wasobtained as a white solid. MS: m/e=372.1 [M+H]⁺.

Example 3456-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 342 g,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.58 mmol) was converted, using 4-aminotetrahydropyran insteadof 2,2,2-trifluoroethylamine, to the title compound (170 mg, 71%) whichwas obtained as a white solid. MS: m/e=414.2 [M+H]⁺.

Example 3466-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamidea) 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid

As described for example 331a,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(4.0 g, 11.6 mmol) was converted, instead of6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methylester, to the title compound (3.8 g, 100%) which was obtained as a lightyellow solid. MS: m/e=331.1 [M−H]⁻.

b)6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamide

As described for example 191,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.3mmol) was converted, instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, usingethanolamine instead of (1R,2R)-2-amino-cyclohexanol hydrochloride(1:1), to the title compound (79 mg, 70%) which was obtained as a whitesolid. MS: m/e=374.0 [M+H]⁺.

Example 3476-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-propyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using (rac)-1-amino-2-propanol instead ofethanolamine, to the title compound (100 mg, 43%) which was obtained asa colourless gum. MS: m/e=388.1 [M+H]⁺.

Example 3486-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-propyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using 3-amino-1-propanol instead of ethanolamine,to the title compound (140 mg, 60%) which was obtained as a white solid.MS: m/e=385.9 [M−H]⁻.

Example 3496-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using 2-amino-2-methyl-1-propanol instead ofethanolamine, to the title compound (110 mg, 45%) which was obtained asa white solid. MS: m/e=402.2 [M+H]⁺.

Example 3506-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2-dimethyl-propyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead ofethanolamine, to the title compound (150 mg, 60%) which was obtained asa white solid. MS: m/e=414.1 [M−H]⁻.

Example 3513-({6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-pyridine-3-carbonyl}-amino)-azetidine-1-carboxylicacid tert-butyl ester

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using 3-amino-1-N-Boc-azetidine instead ofethanolamine, to the title compound (200 mg, 68%) which was obtained asa colourless gum. MS: m/e=483.1 [M−H]⁻.

Example 3526-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamideand6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using rac-trans-2-amino-cyclohexanol hydrochloride(1:1) instead of ethanolamine, to the title compound (170 mg, 70%) whichwas obtained as a colourless gum. MS: m/e=412.1 [M−H]⁻.

Example 3536-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide

As described for example 220,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester(200 mg, 0.58 mmol) was converted, instead of6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester,using 2-amino-1,3-propandiol instead of 3-amino-1-propanol, to the titlecompound (90 mg, 38%) which was obtained as a white solid. MS: m/e=402.1[M−H]⁻.

Example 3546-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using R-(−)-2-amino-1-propanol instead ofethanolamine, to the title compound (80 mg, 34%) which was obtained as awhite solid. MS: m/e=385.9 [M−H]⁻.

Example 3556-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using S-(−)-2-amino-1-propanol instead ofethanolamine, to the title compound (70 mg, 30%) which was obtained as awhite solid. MS: m/e=385.9 [M−H]⁻.

Example 356N-(2-Acetylamino-ethyl)-6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6mmol) was converted, using N-acetylethylenediamine instead ofethanolamine, to the title compound (120 mg, 48%) which was obtained asa white solid. MS: m/e=413.1 [M−H]⁻.

Example 3576-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide

As described for example 346b,6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (150 mg,0.45 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamineinstead of ethanolamine, to the title compound (190 mg, 98%) which wasobtained as a white solid. MS: m/e=424.0 [M−H]⁻.

Example 3586-(3-Pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamidea) 3-Pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester

To a solution of N-chlorosuccinimide (54.7 g, 409 mmol) in DMF (1 L) wasadded pyridine-2-carbaldoxime (50 g, 409 mmol) portionwise and theresulting mixture was then stirred for 64 h at room temperature. To thissolution was then added ethyl 3-(N,N-dimethylamino)acrylate (58.6 g, 409mmol) and triethylamine (82.9 mL, 819 mmol) in chloroform (10 mL) andthe resulting mixture was then stirred for 14 h at room temperature andpoured onto a mixture of ice water and HCl (4 N, 100 mL) and extractedwith ethylacetate. The organic extract was then washed with water,saturated aqueous sodium hydrogen carbonate solution, brine, dried withsodium sulfate, filtered and evaporated. Purification by distillationafforded the title product (58.9 g, 66%) which was obtained as a lightbrown liquid. Bp 125-127° C. at 0.4 mbar. MS: m/e=219.2 [M+H]⁺.

b) 3-Pyridin-2-yl-isoxazole-4-carboxylic acid

As described for example 231, 3-pyridin-2-yl-isoxazole-4-carboxylic acidethyl ester (9.6 g, 44 mmol), instead of(S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionicacid methyl ester, was converted to the title compound (6.5 g, 79%)which was obtained as an off white solid. MS: m/e=189.3 [M−H]⁻.

c) (3-Pyridin-2-yl-isoxazol-4-yl)-methanol

As described for example 323e, 3-pyridin-2-yl-isoxazole-4-carboxylicacid (39.0 g, 200 mmol) was converted, instead of3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid, to the title compound(26.8 g, 76%) which was obtained as a white solid. MS: m/e=177.2 [M]⁺.

e) 6-(3-Pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester

As described for example 84e, (3-pyridin-2-yl-isoxazol-4-yl)-methanol(800 mg, 4.5 mmol) was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (547 mg, 39%) which was obtained as a white solid. MS:m/e=311.9 [M+H]⁺.

f) 6-(3-Pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid

As described for example 358b,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (510mg, 1.6 mmol), instead of 3-pyridin-2-yl-isoxazole-4-carboxylic acidethyl ester, was converted to the title compound (458 mg, 94%) which wasobtained as a white solid. MS: m/e=296.5 [M−H]⁻.

g)6-(3-Pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 162b,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24mmol) was converted using 4-aminotetrahydropyran instead of ethanolamineto the title compound (SiO₂, heptane:ethyl acetate=50:50 to 0:100, 89mg, 99%) which was obtained as a white solid. MS: m/e=381.5 [M+H]⁺.

Example 359N-Isopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 358 g,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24mmol) was converted using isopropylamine instead of4-aminotetrahydropyran to the title compound (76 mg, 95%) which wasobtained as a white solid. MS: m/e=339.1 [M+H]⁺.

Example 360N-Cyclopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 358 g,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24mmol) was converted using cyclopropylamine instead of4-aminotetrahydropyran to the title compound (65 mg, 82%) which wasobtained as a white solid. MS: m/e=337.3 [M+H]⁺.

Example 361N-Cyclopropylmethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 358 g,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24mmol) was converted using aminomethylcyclopropane instead of4-aminotetrahydropyran to the title compound (80 mg, 97%) which wasobtained as a white solid. MS: m/e=351.4 [M+H]⁺.

Example 3626-(3-Pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 358 g,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34mmol) was converted using 2,2,2-trifluoroethylamine instead of4-aminotetrahydropyran to the title compound (83 mg, 65%) which wasobtained as a white solid. MS: m/e=379.3 [M+H]⁺.

Example 363N-(2-Hydroxy-ethyl)-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 358 g,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34mmol) was converted using ethanolamine instead of 4-aminotetrahydropyranto the title compound (82 mg, 72%) which was obtained as a white solid.MS: m/e=341.0 [M+H]⁺.

Example 364 N-Ethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide

As described for example 358 g,6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34mmol) was converted using ethylamine (2 M solution in THF) instead of4-aminotetrahydropyran to the title compound (88 mg, 81%) which wasobtained as a white solid. MS: m/e=325.3 [M+H]⁺.

Example 3656-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamidea) 5-Fluoro-pyridine-2-carbaldehyde oxime

To a solution of 5-fluoro-2-formylpyridine (5.0 g, 41 mmol) andhydroxylamine hydrochloride (3.06 g, 44 mmol) in ethanol (3.2 mL) andwater (9.6 mL) was added ice (18.6 g). Then a solution of NaOH (4.0 g,100 mmol) in water (4.6 mL) was added dropwise over 10 min keeping thetemperature between −5° C. and 5° C. The reaction mixture was thenstirred at room temperature for 30 min. Then HCl (4 N) was added toacidify the mixture and the resulting precipitate was filtered off andwashed with water to afford the title compound (4.41 g, 79%) as a lightbrown solid. MS: m/e=141.0 [M+H]⁺.

b) 3-(5-Fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl ester

To a solution of N-chlorosuccinimide (17.34 g, 130 mmol) in DMF (128 mL)was added 5-fluoro-pyridine-2-carbaldehyde oxime (18.2 g, 130 mmol)portionwise over 2 h at room temperature and as the reaction warmed upto 60° C. the mixture was cooled back to room temperature with anice-water bath and the resulting mixture was then stirred for 64 h atroom temperature. To this solution was then added ethyl3-(N,N-dimethylamino)acrylate (18.6 g, 130 mmol) and triethylamine (36.2mL, 260 mmol) in chloroform (64 mL) and the resulting mixture was thenstirred for 1 h at room temperature and poured onto a mixture of icewater and HCl (4 N, 1 L) and extracted with ethylacetate. The organicextract was then washed with water, saturated aqueous sodium hydrogencarbonate solution, brine, dried with sodium sulfate, filtered andevaporated. Purification by chromatography (SiO₂,heptane:ethylacetate=100:0 to 1:1) afforded the title product (21.96 g,72%) which was obtained as a yellow solid. MS: m/e=237.1 [M+H]⁺.

ci) [3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-yl]-methanol

To a solution of 3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acidethyl ester (1.0 g, 4.23 mmol) in THF (52 mL) was added portionwiselithiumaluminiumhydride (89 mg, 2.33 mmol) at 0° C. and the reactionmixture was stirred at room temperature for 1 h. The mixture was thencooled to 0° C. and water (88 μL) added followed by sodium hydroxide(15% solution, 88 μL) and then again water (264 μL) and the mixture thenstirred overnight at room temperature. The precipitate was then filteredoff and washed with THF. The combined washings and filtrate were thenevaporated. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 1:1) afforded the title compound (249 mg, 30%) whichwas obtained as a light yellow solid. MS: m/e=195.1 [M+H]⁺.

Or alternatively via

cii) 3-(5-Fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid

As described for example 358b,3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl ester (1.0g, 4.23 mmol) was converted, instead of3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester, to the titlecompound (587 mg, 67%) which was obtained as a dark brown solid. MS:m/e=207.1 [M−H]⁻.

ciii) [3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-yl]-methanol

As described for example 358c,3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid (562 mg, 2.7 mmol)was converted, instead of 3-pyridin-2-yl-isoxazole-4-carboxylic acid, tothe title compound (367 mg, 70%) which was obtained as an off whitesolid. MS: m/e=195.2 [M+H]⁺.

d) 6-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acidmethyl ester

As described for example 84e,[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-methanol (561 mg, 2.9 mmol)was converted, instead of[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol, to the titlecompound (586 mg, 61%) which was obtained as a white solid. MS:m/e=330.0 [M+H]⁺.

e) 6-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid

As described for example 365cii,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid methylester (313 mg, 0.9 mmol) was converted,3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl ester, tothe title compound (251 mg, 84%) which was obtained as a white solid.MS: m/e=328.3 [M−H]⁻.

f)6-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide

As described for example 98b,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, instead of6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,using 4-aminotetrayhdropyran instead of 2,2,2-trifluoroethylamine, tothe title compound (79 mg, 79%) which was obtained as an off whitesolid. MS: m/e=399.1 [M+H]⁺.

Example 3666-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide

As described for example 365f,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, using isopropylamine instead of4-aminotetrayhdropyran, to the title compound (67 mg, 75%) which wasobtained as an off white solid. MS: m/e=357.1 [M+H]⁺.

Example 367Cyclopropyl-6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 365f,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, using cyclopropylamine instead of4-aminotetrayhdropyran, to the title compound (64 mg, 73%) which wasobtained as a white solid. MS: m/e=355.2 [M+H]⁺.

Example 3686-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide

As described for example 365f,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, using 2-amino-2-methyl-1-propanol insteadof 4-aminotetrayhdropyran, to the title compound (60 mg, 62%) which wasobtained as a white solid. MS: m/e=387.2 [M+H]⁺.

Example 3696-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2,2,2-trifluoro-ethyl)-nicotinamide

As described for example 365f,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, using 2-amino-2-methyl-1-propanol insteadof 4-aminotetrayhdropyran, to the title compound (80 mg, 81%) which wasobtained as a white solid. MS: m/e=397.1 [M+H]⁺.

Example 3706-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide

As described for example 365f,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, using aminoethanol instead of4-aminotetrayhdropyran, to the title compound (34 mg, 38%) which wasobtained as a white solid. MS: m/e=359.1 [M+H]⁺.

Example 371Ethyl-6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamide

As described for example 365f,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, using ethylamine (2 M solution in THF)instead of 4-aminotetrayhdropyran, to the title compound (52 mg, 61%)which was obtained as a white solid. MS: m/e=343.1 [M+H]⁺.

Example 3726-[3-(5-Fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-methyl-nicotinamide

As described for example 365f,6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79mg, 0.25 mmol) was converted, using methylamine (2 M solution in THF)instead of 4-aminotetrayhdropyran, to the title compound (55 mg, 67%)which was obtained as a white solid. MS: m/e=329.2 [M+H]⁺.

We claim:
 1. A compound of formula I

wherein X is O or NH; R¹ is phenyl, optionally substituted with 1, 2 or3 halo, R² is H or CH₃ or CF₃; R³, R⁴, R⁵, and R⁶ are H; C₁₋₇alkyl,optionally substituted with one or more halo, cyano, or hydroxy,C₁₋₇alkoxy, optionally substituted with one or more halo, CN, halo, NO₂,S—C₁₋₇alkyl, S(O)—C₁₋₇alkyl benzyloxy, optionally substituted with oneor more E, —C(O)—R^(a), wherein R^(a) is hydroxy, C₁₋₇alkoxy, C₁₋₇alkyl,phenoxy or phenyl, 3- to 7-membered heterocyclyl, optionally substitutedwith one or more A, —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are eachindependently H, C₁₋₇alkyl, optionally substituted with one or morehalo, methyl, —(CH₂)_(t)-hydroxy, or cyano, —(CH₂)_(t)—C₃₋₇cycloalkyl,optionally substituted by one or more B, and t is 0, 1, 2, 3, 4, 5 or 6,—(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3, 4, 5 or 6,—CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl or C₁₋₄alkyl, andR^(ii) is H or C₁₋₇alkyl, —S(O)₂—C₁₋₇alkyl, —S(O)₂—C₃₋₇cycloalkyl,—(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3, and R^(iii) is H orC₁₋₇alkyl, —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl, each optionallysubstituted by one or more E, and wherein w is 0, 1, 2, 3, or 4,—(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and whereinheterocyclyl is optionally substituted by one or more oxo, C₁₋₇alkyl,C₃₋₇cycloalkyl, optionally substituted with one or more B, CN, benzyl,optionally substituted with one or more E, —(CH₂)_(y)—C(O)R^(iv),wherein y is 0, 1, 2, 3 or 4, and R^(iv) is hydroxy, C₁₋₇alkyl, orC₁₋₇alkoxy, —(CH₂)_(z)—C(O)NR^(v)R^(vi),—(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or—(CH₂)_(z)NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z is 0, 1, 2, 3 or 4,and R^(v) and R^(vi) are independently hydrogen, C₁₋₇alkyl, optionallysubstituted by one or more halo, OH or CN, C₃₋₇cycloalkyl, optionallysubstituted by one or more B, 5- or 6-membered heterocyclyl, optionallysubstituted by one or more A, or R^(v) and R^(vi) together with thenitrogen to which they are bound form a 5- or 6-memberedheterocycloalkyl, optionally substituted by one or more A, or R^(b) andR^(c) together with the nitrogen to which they are bound form aheterocyclyl or heteroaryl moiety, optionally substituted with one ormore A, or R^(b) and R^(c) together with the nitrogen to which they arebound form a 7- to 12-membered spirocyclic heterocycle, optionallysubstituted with one or more A; with the proviso that R^(b) and R^(c)are not simultaneously H, and at least one of R³, R⁵, and R⁶ being otherthan hydrogen; A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,C₁₋₇hydroxyalkyl, halo, or CN; B is halo, hydroxy, CN, C₁₋₄alkyl,benzyloxy, or C₁₋₄haloalkyl; and E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl,C₁₋₇alkoxy, C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl,C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl; with the proviso that at least one ofR³, R⁵, and R⁶ being other than hydrogen; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein R³ and R⁶are H, halo, CN or C₁₋₇alkyl.
 3. The compound of claim 1, wherein R⁴ isH, C₁₋₇alkyl, optionally substituted with one or more halo, cyano, orhydroxy, C₁₋₇alkoxy, optionally substituted with one or more halo, CN,halo, NO₂, S—C₁₋₇alkyl, S(O)—C₁₋₇alkyl benzyloxy, optionally substitutedwith one or more E, —C(O)—R^(a), wherein R^(a) is hydroxy, C₁₋₇alkoxy,C₁₋₇alkyl, phenoxy or phenyl, 3- to 7-membered heterocyclyl, optionallysubstituted with one or more A, —C(O)—NR^(b)R^(c), wherein R^(b) andR^(c) are each independently H, C₁₋₇alkyl, optionally substituted withone or more halo, methyl, —(CH₂)_(t)-hydroxy, or cyano,—(CH₂)_(t)—C₃₋₇cycloalkyl, optionally substituted by one or more B, andt is 0, 1, 2, 3, 4, 5 or 6, —(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3,4, 5 or 6, —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl orC₁₋₄alkyl, and R^(ii) is H or C₁₋₇alkyl, —S(O)₂—C₁₋₇alkyl—S(O)₂—C₃₋₇cycloalkyl —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3,and R^(iii) is H or C₁₋₇alkyl, —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl,each optionally substituted by one or more E, and wherein w is 0, 1, 2,3, or 4, —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4, andwherein heterocyclyl is optionally substituted by one or more oxo,C₁₋₇alkyl, C₃₋₇cycloalkyl, optionally substituted with one or more B,CN, benzyl, optionally substituted with one or more E,—(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4, and R^(iv) ishydroxy, C₁₋₇alkyl, or C₁₋₇alkoxy, —(CH₂)_(z)—C(O)NR^(v)R^(vi),—(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or(CH₂)_(z)NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z is 0, 1, 2, 3 or 4 andR^(v) and R^(vi) are independently hydrogen, C₁₋₇alkyl, optionallysubstituted by one or more halo, OH or CN, C₃₋₇cycloalkyl, optionallysubstituted by one or more B, 5- or 6-membered heterocyclyl, optionallysubstituted by one or more A, or R^(v) and R^(vi) together with thenitrogen to which they are bound form a 5- or 6-memberedheterocycloalkyl, optionally substituted by one or more A, or R^(b) andR^(c) together with the nitrogen to which they are bound form aheterocyclyl or heteroaryl moiety, optionally substituted with one ormore A, or R^(b) and R^(c) together with the nitrogen to which they arebound form a 7- to 12-membered spirocyclic heterocycle, optionallysubstituted with one or more A; with the proviso that R^(b) and R^(c)are not simultaneously H, A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy,C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, halo, or CN; B is halo, hydroxy, CN,C₁₋₄alkyl, benzyloxy, or C₁₋₄haloalkyl; and E is halo, CN, NO₂, hydroxy,C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl,C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl; or a pharmaceutically acceptable saltthereof.
 4. The compound of claim 1, wherein R⁴ is —C(O)—NR^(b)R^(c),wherein R^(b) and R^(c) are each independently H, C₁₋₇alkyl, optionallysubstituted with one or more halo, methyl, —(CH₂)_(t)-hydroxy, or cyano,—(CH₂)_(t)—C₃₋₇cycloalkyl, optionally substituted by one or more B, andt is 0, 1, 2, 3, 4, 5 or 6, —(CH₂)_(u)—O—C₁₋₇alkyl, wherein u is 2, 3,4, 5 or 6, —CHR^(i)—C(O)OR^(ii), wherein R^(i) is H, benzyl orC₁₋₄alkyl, and R^(ii) is H or C₁₋₇alkyl, —S(O)₂—C₁₋₇alkyl,—S(O)₂—C₃₋₇cycloalkyl, —(CH₂CH₂O)_(v)R^(iii), wherein v is from 1 to 3,and R^(iii) is H or C₁₋₇alkyl, —(CH₂)_(w)-heteroaryl or —(CH₂)_(w)-aryl,each optionally substituted by one or more E, and wherein w is 0, 1, 2,3, or 4, —(CH₂)_(x)-heterocyclyl, wherein x is 0, 1, 2, 3 or 4, andwherein heterocyclyl is optionally substituted by one or more oxo,C₁₋₇alkyl, C₃₋₇cycloalkyl, optionally substituted with one or more B,CN, benzyl, optionally substituted with one or more E,—(CH₂)_(y)—C(O)R^(iv), wherein y is 0, 1, 2, 3 or 4, and R^(iv) ishydroxy, C₁₋₇alkyl, or C₁₋₇alkoxy, —(CH₂)_(z)—C(O)NR^(v)R^(vi),—(CH₂)_(z)NR^(v)R^(vi)—C(O)—C₁₋₇alkyl or—(CH₂)_(z)NR^(v)R^(vi)—C(O)—O—C₁₋₇alkyl, wherein z is 0, 1, 2, 3 or 4,and R^(v) and R^(vi) are independently hydrogen, C₁₋₇alkyl, optionallysubstituted by one or more halo, OH or CN, C₃₋₇cycloalkyl, optionallysubstituted by one or more B, 5- or 6-membered heterocyclyl, optionallysubstituted by one or more A, or R^(v) and R^(vi) together with thenitrogen to which they are bound form a 5- or 6-memberedheterocycloalkyl, optionally substituted by one or more A, or R^(b) andR^(c) together with the nitrogen to which they are bound form aheterocyclyl or heteroaryl moiety, optionally substituted with one ormore A, or R^(b) and R^(c) together with the nitrogen to which they arebound form a 7- to 12-membered spirocyclic heterocycle, optionallysubstituted with one or more A with the proviso that R^(b) and R^(c) arenot simultaneously H, A is hydroxy, oxo, C₁₋₇alkyl, C₁₋₇alkoxy,C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, halo, or CN; B is halo, hydroxy, CN,C₁₋₄alkyl, benzyloxy, or C₁₋₄haloalkyl; and E is halo, CN, NO₂, hydroxy,C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl,C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl; or a pharmaceutically acceptable saltthereof.
 5. The compound of claim 1, wherein R⁴ is H, C₁₋₇alkyl,optionally substituted with one or more halo, cyano, or hydroxy,C₁₋₇alkoxy, optionally substituted with one or more halo, CN, halo, NO₂,S—C₁₋₇alkyl, S(O)—C₁₋₇alkyl, or benzyloxy, optionally substituted withone or more E, and E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy,C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, orC₃₋₇cycloalkyl; or a pharmaceutically acceptable salt thereof.
 6. Thecompound of claim 1, wherein R⁴ is —C(O)—R^(a), wherein R^(a) ishydroxy, C₁₋₇alkoxy, C₁₋₇alkyl, phenoxy or phenyl.
 7. The compound ofclaim 1, wherein R⁴ is benzyloxy optionally substituted with one or moreE and E is halo, CN, NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl,C₁₋₇hydroxyalkyl, C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl. 8.The compound of claim 1, wherein R⁴ is 3- to 7-membered heterocyclyl,optionally substituted with one or more A, wherein A is hydroxy, oxo,C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, halo, or CN; ora pharmaceutically acceptable salt thereof.
 9. The compound of claim 1,wherein R⁴ is oxethenanyl substituted with one OH.
 10. The compound ofclaim 1, wherein R⁵ is H, C₁₋₇alkyl, optionally substituted by one ormore halo, hydroxy or CN, benzyloxy, optionally substituted with one ormore E, 3- to 7-membered heterocyclyl, optionally substituted with oneor more A, —C(O)—NR^(b)R^(c), wherein R^(b) and R^(c) are eachindependently H, or 3-7-membered heterocycloalkyl, optionallysubstituted with one or more A, and A is hydroxy, oxo, C₁₋₇alkyl,C₁₋₇alkoxy, C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, halo, or CN; E is halo, CN,NO₂, hydroxy, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl,C₁₋₇cyanoalkyl, C₁₋₇haloalkoxy, or C₃₋₇cycloalkyl.
 11. The compound ofclaim 10, wherein R⁵ is H or trifluoromethyl.
 12. The compound of claim1, wherein R⁴ is H.
 13. The compound of claim 1, wherein R⁴ is CN. 14.The compound of claim 1, wherein R⁴ is halo.
 15. The compound of claim1, wherein R⁴ is NO₂.
 16. The compound of claim 1, wherein R¹ is phenyloptionally substituted with one or two halo.
 17. The compound of claim1, wherein R² is methyl or trifluoromethyl.
 18. The compound of claim 1,wherein R³ is H, halo, CN, or C₁₋₇alkyl.
 19. The compound of claim 18,wherein R³ is H, CN, or C₁₋₄alkyl.
 20. The compound of claim 19, whereinR³ is H, CN, or methyl.
 21. The compound of claim 1, wherein R⁶ is H,halo, CN, or C₁₋₇alkyl.
 22. The compound of claim 21, wherein R⁶ is H,halo, or C₁₋₄alkyl.
 23. The compound of claim 22, wherein R⁶ is H, Br,or C₁₋₄alkyl.
 24. The compound of claim 23, wherein R⁶ is H, Br ormethyl.
 25. The compound of claim 1, wherein R⁴ is C(O)NR^(b)R^(c),wherein R^(b) and R^(c) together with the N to which they are bound forma heterocyclyl moiety optionally substituted with one or more A.
 26. Thecompound of claim 1, wherein R⁴ is C(O)NR^(b)R^(c), wherein R^(b) andR^(c) together with the N to which they are bound form a 7- to12-membered spirocyclic heterocycle optionally substituted with one ormore A.
 27. The compound of claim 1, wherein R³, R⁴, R⁵, and R⁶ are notsimultaneously H.
 28. The compound of claim 1, selected from the groupconsisting of:2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine;4-benzyloxy-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine;1-methyl-2′-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-1,2,3,6-tetrahydro-[4,4′]bipyridinyl;2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide;2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-isonicotinamide;2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide;6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinicacid;N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinamide;6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-4-trifluoromethyl-nicotinamide;5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methylester;5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamideand a pharmaceutically acceptable salt or ester thereof.
 29. Thecompound of claim 1, selected from the group consisting of:5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide;5-bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide;5-bromo-N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide;N-isopropyl-5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide;2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid ethylester;6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carbonitrile and apharmaceutically acceptable salt or ester thereof.
 30. The compound ofclaim 1 wherein said compound is5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamideor a pharmaceutically acceptable salt thereof.